Download Cross-Talk Between Cardiac Muscle and Coronary Vasculature

Physiol Rev 86: 1263–1308, 2006;
doi:10.1152/physrev.00029.2005.
Cross-Talk Between Cardiac Muscle and Coronary Vasculature
NICO WESTERHOF, CHRISTA BOER, REGIS R. LAMBERTS, AND PIETER SIPKEMA
Laboratory for Physiology and Department of Anesthesiology, Institute for Cardiovascular Research Vrije
Universiteit, VU University Medical Center, Amsterdam, The Netherlands
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I. Introduction
II. The Cardiac Muscle and the Coronary Vasculature
A. Functional arrangement of the cardiac muscle and the coronary circulation
B. Coronary pressure-flow relationships
C. Summary
III. The Cardiac Muscle Affects the Coronary Vasculature
A. Cardiac muscle and coronary flow in diastole
B. Cardiac contraction and coronary flow in systole
C. Models explaining the diastolic-systolic changes of the vasculature
D. Applications and limitations of the models
E. Cardiac contraction augments coronary flow
F. Effects of cardiac muscle on the coronary vasculature: summary
IV. The Coronary Vasculature Affects the Cardiac Muscle
A. Coronary flow and cardiac muscle in diastole
B. Coronary flow and cardiac muscle in systole
C. Effects of coronary vasculature on cardiac muscle: summary
V. Role of the Extracellular Matrix in Cross-Talk
A. Theoretical suggestions
B. Experimental findings
C. Summary
VI. Conclusions
A. Cardiac muscle affects the coronary vasculature
B. Coronary vasculature affects the cardiac muscle
C. Extracellular matrix
Westerhof, Nico, Christa Boer, Regis R. Lamberts, and Pieter Sipkema. Cross-Talk Between Cardiac Muscle
and Coronary Vasculature. Physiol Rev 86: 1263–1308, 2006; doi:10.1152/physrev.00029.2005.—The cardiac muscle
and the coronary vasculature are in close proximity to each other, and a two-way interaction, called cross-talk,
exists. Here we focus on the mechanical aspects of cross-talk including the role of the extracellular matrix. Cardiac
muscle affects the coronary vasculature. In diastole, the effect of the cardiac muscle on the coronary vasculature
depends on the (changes in) muscle length but appears to be small. In systole, coronary artery inflow is impeded,
or even reversed, and venous outflow is augmented. These systolic effects are explained by two mechanisms. The
waterfall model and the intramyocardial pump model are based on an intramyocardial pressure, assumed to be
proportional to ventricular pressure. They explain the global effects of contraction on coronary flow and the effects
of contraction in the layers of the heart wall. The varying elastance model, the muscle shortening and thickening
model, and the vascular deformation model are based on direct contact between muscles and vessels. They predict
global effects as well as differences on flow in layers and flow heterogeneity due to contraction. The relative
contributions of these two mechanisms depend on the wall layer (epi- or endocardial) and type of contraction
(isovolumic or shortening). Intramyocardial pressure results from (local) muscle contraction and to what extent the
interstitial cavity contracts isovolumically. This explains why small arterioles and venules do not collapse in systole.
Coronary vasculature affects the cardiac muscle. In diastole, at physiological ventricular volumes, an increase in
coronary perfusion pressure increases ventricular stiffness, but the effect is small. In systole, there are two
mechanisms by which coronary perfusion affects cardiac contractility. Increased perfusion pressure increases
microvascular volume, thereby opening stretch-activated ion channels, resulting in an increased intracellular Ca2⫹
transient, which is followed by an increase in Ca2⫹ sensitivity and higher muscle contractility (Gregg effect).
Thickening of the shortening cardiac muscle takes place at the expense of the vascular volume, which causes
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build-up of intracellular pressure. The intracellular pressure counteracts the tension generated by the contractile
apparatus, leading to lower net force. Therefore, cardiac muscle contraction is augmented when vascular emptying
is facilitated. During autoregulation, the microvasculature is protected against volume changes, and the Gregg effect
is negligible. However, the effect is present in the right ventricle, as well as in pathological conditions with
ineffective autoregulation. The beneficial effect of vascular emptying may be reduced in the presence of a stenosis.
Thus cardiac contraction affects vascular diameters thereby reducing coronary inflow and enhancing venous
outflow. Emptying of the vasculature, however, enhances muscle contraction. The extracellular matrix exerts its
effect mainly on cardiac properties rather than on the cross-talk between cardiac muscle and coronary circulation.
I. INTRODUCTION
FIG. 1. Mechanisms of cross-talk in
the heart, excluding the contribution of
neurohumoral regulation.
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Coronary perfusion is essential for cardiac function
and is regulated in a number of ways. These can be
divided into extrinsic, such as the humoral-nervous regulation, and intrinsic, i.e., autoregulation. Autoregulation is
the intrinsic tendency of the vasculature to maintain constant blood flow despite changes in perfusion pressure
(190) and does not include the effects of extrinsic nerves
or hormones (124). The matching of coronary blood flow
to cardiac metabolism determines the plateau of the autoregulation and has recently been reviewed by Tune et
al. (408). Autoregulation is not restricted to cardiac muscle as it also acts in other organs such as kidney and
brain. However, for the vasculature embedded in cardiac
and skeletal muscle another component plays a role,
namely, the mechanical interaction of the contracting
muscle and the vasculature. This interaction results in
decreased coronary arterial inflow and increased coronary venous outflow as the cardiac muscle contracts.
Inversely, the coronary vasculature itself and the vascular
flow and pressure have an effect on cardiac muscle and its
contraction. The role of the vascular and the endocardial
endothelium in this effect and their related signaling pathways have recently been reviewed (55). Neurohumoral
control of the coronary vasculature, the effects of limitations in oxygen supply, and pathology (such as long-term
adaptive effects of vessel and cardiac muscle interaction)
are not discussed in this review.
Earlier reviews of coronary hemodynamics have provided substantial information about the coronary circulation (124, 151, 175, 226, 233, 235, 376, 377, 448, 458).
However, limited attention has been given to the mutual
interaction (cross-talk) of the cardiac muscle and the
coronary vasculature. Modern measurement techniques,
presently allowing for the noninvasive determination of
human cardiac perfusion and cardiac muscle contraction
(35, 176, 182, 269), now make it possible to study crosstalk in the clinical setting. These novel techniques together with a better knowledge of cross-talk will help to
improve the understanding of pathological changes, adaptations, and the effects of therapeutic interventions (3,
105, 135, 136, 180, 222, 258, 300, 319, 328, 455).
The multiple mutual interactions between the coronary vasculature and the cardiac muscle can be divided
into mechanical (including the role of the extracellular
matrix) and mediator-based mechanisms (Fig. 1). This
review concentrates on the acute mechanical factors that
contribute to the two-way interactions between cardiac
muscle and vasculature, which we will call mechanical
cross-talk. On the one hand, the contracting cardiac muscle generates force and ventricular pressure, shortens and
thickens, and increases in stiffness. These changes affect
the coronary vasculature and coronary flow. On the other
hand, increased vascular filling increases the vascular
diameters that affect the neighboring cardiac muscle
cells. Furthermore, when the smooth muscle tone
changes it affects the mechanical properties of the vascular wall. Both vascular effects influence cardiac muscle
contraction.
We start with an introduction on the functional arrangement of vasculature and cardiac muscle and then
discuss the effect of the cardiac muscle on the coronary
vasculature. Subsequently, we review the effect of the
coronary vasculature on cardiac muscle. These interactions depend on the mechanical characteristics of the
vasculature (e.g., as affected by vasomotor tone), the
cardiac muscle (e.g., cardiac muscle contractility), and
the extracellular matrix. The published models are introduced and their description of mechanical cross-talk is
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
discussed in relation to the existing experimental data.
The role of the extracellular matrix on cardiac function
has been studied (28, 276, 403) and recently reviewed
(189). However, the role of the extracellular matrix in
mechanical cross-talk is largely unknown, but is discussed as well.
Most examples in this review pertain to the left ventricle; the right ventricle is mentioned, when pertinent.
II. THE CARDIAC MUSCLE AND THE
CORONARY VASCULATURE
The coronary circulation is a system of branching
vessels that can be divided into the epicardial arteries and
veins and the intramyocardial vessels. The mechanical
cross-talk between cardiac muscle and vessels mainly
takes place at the level of the intramyocardial vessels. The
intramyocardial vessels can be further divided into the
transmural vessels and the microcirculation. Information
about the anatomy of the coronary vasculature and its
integration in the muscular network can be found in a
number of publications (46, 150, 217, 331, 360, 376, 401,
404, 409a). The detailed structure of coronary arteries, the
capillary network, and the venular system and their relation to function has been described by Kassab and coworkers (213–219, 409a). Currently, Spaan et al. (381) are
developing a new method where the coronary microcirculatory morphology in situ can be visualized, including
the relationship with the cardiac muscle. Pressure measurements in differently sized arteries and arterioles have
indicated that under normal conditions, 45–50% of total
coronary vascular resistance resides in vessels larger than
100 ␮m (279). Details about the coronary arterial microcirculation and its regulation can be found elsewhere (71,
75). The important role of the coronary microcirculation
in coronary disease has been reviewed by Cecchi et al.
(65).
The number of resistance vessels in the subendocardium is somewhat higher than in the subepicardium (402).
As a result of this anatomical difference, the flow in
diastole is ⬃10% higher in subendocardial than in subepicardial layers. The greater impeding effect of cardiac
muscle contraction on arterial flow in subendocardial
compared with subepicardial layers is thus, partly, compensated for by the difference in the number of resistance
vessels. Differences in mean flow in the layers are generally small under physiological conditions, but may exist
(137).
A homogeneous distribution of flow, cardiac metabolism, and muscle function as proposed earlier (414) is
probably too simple a view. Local coronary perfusion
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differs, and this heterogeneity increases towards the microcirculation (22, 23, 29, 31, 170, 236, 239, 349, 410, 409a),
but this is not related to certain fixed regions (30, 209).
Heterogeneity in flow between control and moderate dilation differs little (99) but is different during maximal
vasodilation (23). This heterogeneity depends on perfusion pressure (127) and on the perfusate (285); therefore,
it is only partially dependent on the anatomy. Heterogeneity of flow is present in ischemia in the patient (344).
Oxygen consumption, glucose uptake, glycolytic enzyme
activity, and oxygen delivery are related and also heterogeneously distributed (6, 158, 179, 252, 372). In addition to
flow heterogeneity, flow regulation (193), metabolic control of flow (98), vasomotion (400), microvascular coronary ␣-adrenergic vasoconstriction (77), and responses to
drugs (78, 236, 265) are all heterogeneously distributed.
Heterogeneity is greatest at the submillimeter scale (30),
but it has not been established if, on this scale, cardiac
muscle contraction is also heterogeneously distributed in
the heart wall (33). Magnetic resonance imaging (MRI)
and positron emission tomography (PET), and even ultrasound, can provide insight into heterogeneity of flow,
muscle function, local oxygen consumption, etc. (165,
344). There is also variation in flow with time called
“twinkling” (29, 228), resulting from vasomotion. It may
therefore be expected that heterogeneity also exists in
mechanical cross-talk.
B. Coronary Pressure-Flow Relationships
Coronary pressure-flow relationships are strongly determined by autoregulation. Furthermore, flow reserve
depends on autoregulation, and the supply-to-demand ratio assumes that flow is related to muscle metabolism and
is negligible in systole. All three characterizations depend
on vasomotor tone and cardiac contractility and thus on
the mechanical properties of the vasculature and the cardiac muscle. We show below that the mechanical properties of the vasculature and cardiac muscle affect mechanical cross-talk.
1. Autoregulation
Autoregulation (Fig. 2) is the capacity of an organ to
regulate its own blood flow when perfusion pressure is
challenged (293, 338). Cardiac muscle plays an important
role in coronary autoregulation: blood flow adjusts to
muscle metabolism, and in the physiological range flow is
rather independent of perfusion pressure. The level of the
plateau of the autoregulation curve is related to the metabolic state of the heart (293, 306). There are several local
autoregulatory control mechanisms that match blood
flow to activity of the tissue. By changes in the diameter
of mainly the arterioles, where vascular resistance resides
(74, 306, 338, 446), flow can be adjusted within a typical
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A. Functional Arrangement of the Cardiac Muscle
and the Coronary Circulation
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cle can affect smooth muscle tone. A single responsible
mediator cannot be distinguished. Metabolites such as
adenosine and carbon dioxide play a role, while pH and
ions, oxygen, and K⫹-ATP channels also appear to be
involved, depending on the conditions (38, 39, 56, 91–93,
112, 116, 124, 181, 225, 294). Metabolic autoregulation is
an aspect of cross-talk. However, the mechanical aspect is
indirect, since a change in vasomotor tone affects vascular mechanics and thus mechanical cross-talk.
4. Endothelium-based control
response time of a few seconds (365, 416). Changes in the
diameter of the microvessels in part result from the
smooth muscle properties per se, myogenic control, and
in part result from factors released from the cardiac muscle, metabolic control, and the endothelium-based control.
2. Myogenic control
The vascular transmural blood pressure leads to
stress in the circumferential direction of the vessel wall
and is called “hoop stress.” This pressure-induced vascular control forms the basis of the myogenic response and
results in a change in vessel diameter to maintain a constant hoop stress, as shown in the coronary arterioles of
the pig and the human (191, 192, 255, 256, 298). After an
increase in the intraluminal pressure (Fig. 3), the diameter
initially follows passively, and subsequently active
smooth muscle contraction causes the diameter to decrease, leading to normalization of the wall stress. In
response to decreased pressure, the opposite effect takes
place. The myogenic response resides in the smooth muscle itself, since it is present in vessels without endothelium (254). The effect of myogenic regulation on the
resistance distribution of the coronary system has been
modeled (86). The myogenic autoregulation is based on
hoop stress determining vascular tone and is not the
result of mechanical cross-talk. However, vasomotor tone
does affect cross-talk.
3. Metabolic control
Where the vasculature is in close contact with the
cardiac muscle, mediators released from the cardiac musPhysiol Rev • VOL
FIG. 3. The myogenic response. An increase in pressure increases
vessel diameter and wall stress, causing smooth muscle contraction that
reduces the diameter to a size smaller than at the lower, starting,
pressure and restores wall stress.
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FIG. 2. Autoregulation maintains flow during constant metabolism
and adapts flow to altered metabolism. Over the autoregulation range,
i.e., the plateau of the autoregulation curve, flow is rather constant for a
range of perfusion pressures. The level of the plateau is related to the
metabolic state of the heart. The dashed line indicates maximal pharmacological vasodilation. The dotted line shows the maximal physiological dilation, which is smaller than can be reached pharmacologically.
The flow reserve is given by the ratio (B ⫹ A)/A (76, 113).
Shear stress is caused by friction between the flow of
blood and the vascular wall, and it acts in the axial
(longitudinal) direction on the endothelial cells. The main
mediator released from the endothelium affecting the
smooth muscle cells is NO. This flow-induced control of
vascular tone adjusts the diameters such that the shear
stress is maintained constant, e.g., increased flow causes
an increase in vessel diameter (240 –242, 253, 257). A
relationship exists between myogenic and endotheliumbased control (255). It was recently shown that an endothelium-derived hyperpolarizing factor also plays a role in
vivo (453). In addition, there is metabolic communication
between cardiac muscle and endothelial cells (56). Chilian et al. (74) concluded that a significant part of the
arterial tree, with vessels larger than the smallest arterioles, also contributes to total coronary vascular resistance, implying a role of endothelium-based regulation in
coronary vascular tone and resistance. The vascular bed
acts as a functional syncytium through electrical coupling
of vascular cells (100, 335, 357), and changes in coronary
resistance take place through “coordinated” action. An
elegant concept integrating myogenic, metabolic, and
flow-dependent regulation was published by Jones et al.
(192), and this was modeled by Cornelissen et al. (85).
We conclude that endothelium-based control, by affecting smooth muscle tone and vascular mechanics,
plays a role in mechanical cross-talk.
All three autoregulatory mechanisms, which to a certain extent are redundant, act together, and the interaction is complex. However, an order of action can be
distinguished. If perfusion pressure changes, the endothe-
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lium-mediated regulation and the myogenic response will
be activated first, and then, if cardiac muscle contractility
and metabolism increase, the metabolic regulation will
follow. With a change in cardiac metabolism, the metabolic regulation will be initiated first. The myogenic response will then follow, and the increased flow will result
in flow-mediated dilation through increased shear stress.
5. Autoregulation gain
Autoregulation gain (G) is a measure of the strength
of autoregulation and can be calculated as (see Fig. 4)
with ⌬Q/⌬P being the slope of the regulated mean pressure-mean flow relationship and Q/P the slope of the line
connecting the point of determination and the origin of
the graph, as a (theoretical) measure of the resistance. It
can be seen that for perfect autoregulation, the gain
equals one and for no autoregulation, assuming the pressure-flow relationship would go through the origin, the
gain equals zero. Autoregulation gain can be plotted as a
function of pressure to obtain the range of regulation and
its dependence on perfusion pressure. The assumption
that the not-regulated pressure-flow relationship (dashed
line of Fig. 4) goes through the origin has been challenged
(see sect. IIIA1).
6. Flow reserve
Flow reserve at any given pressure is the difference
between regulated and not-regulated flow. As such, it is
influenced by changes in metabolism (which change the
autoregulatory plateau) as well as by a stenosis, which
changes the maximal flow. The functional behavior of a
coronary artery stenosis is difficult to estimate from images (angiography, MRI, and even multislice computed
tomography). Therefore, interventions combined with
measurements of pressure or pressure gradient and/or
flow have been proposed to quantify the functional sever-
7. Coronary flow reserve
Flow reserve is the ratio of maximal flow obtained by
coronary vasodilation and the resting or reference flow
[see Fig. 2, ratio (A⫹B)/A] (97, 145–148, 234, 236, 271).
This ratio is reduced when a stenosis is present. The
microcirculatory resistance and the maximal dilatory capacity of the microcirculation, together with the severity
of the stenosis, determine the resting flow and the maximal flow. Thus the coronary flow reserve (CFR) depends
not only on the severity of the stenosis but also on the
state of the microcirculation. A short coronary occlusion
may be used to obtain vasodilation. However, this physiological dilation may be less than when vasodilation is
obtained pharmacologically (113, 137, 259). With a larger
flow than in physiological dilation, a larger estimate of
CFR is obtained (see Fig. 2). Since the myogenic response
takes place in 15 or more seconds (365), and the metabolic control starts even later, this sets the minimally
required duration of the occlusion (83). A value of CFR
⬎2 is used as cut-off value; a CFR ⬍2 implies a functional
stenosis.
In the beating heart, mean flow and mean maximal
flow are affected by cardiac muscle contraction. When the
CFR is determined in diastole only (280), the confounding
effect of cardiac contraction is not included in the results.
However, vascular emptying and compliance (capacitance) may then play a role, but their effects can be
corrected (24).
Bishop and Samady (45) recently reviewed the subject of CFR. Hoffman (171, 172) discussed the limitations
of and the difficulties with CFR. The main limitations are
that the function of the microcirculation is not accounted
for, e.g., maximal dilation is often not achieved (113, 149).
Furthermore, the CFR only gives global information,
whereas flow is heterogeneously distributed (22).
We conclude that the CFR depends on the microcirculation, which is affected by cardiac muscle contraction
and thus depends on mechanical cross-talk.
8. Fractional flow reserve
Another functional estimate of the severity of a stenosis is the fractional flow reserve (FFR) (320). The FFR
is the ratio of the maximal flow (Qmax,s) in the bed perfused by the stenosed artery and the maximal flow in a
normal, unstenosed area (Qmax,n). Therefore
FIG. 4. The definition of autoregulation gain is as follows: G ⫽ 1 ⫺
slopeA/slopeU ⫽ 1 ⫺ (⌬Q/⌬P)/(Q/P) ⫽ 1 ⫺ (⌬Q/Q)/(⌬P/P). Gain depends
on the working point.
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FFR ⫽ Qmax,s/Qmax,n ⫽ 关共Pd ⫺ Pv兲/Rst兴/关共Pprox
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G ⫽ 1 ⫺ 共⌬Q/⌬P兲/共Q/P兲 ⫽ 1 ⫺ 共⌬Q/Q兲/共⌬P/P兲
ity of a stenosis (145–148, 281, 310). Since this characterization requires pressure and/or flow measurements, including the pressure distal of the stenosis, simpler characterizations such as coronary flow reserve and fractional
flow reserve have been introduced.
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stress or systolic pressure and heart rate (337, 345, 386).
When expressed per heart beat, the area under the systolic part of ventricular or aortic pressure can be used as
an estimate of oxygen demand. In this way, we can apply
the so-called supply-to-demand ratio (173), which is directly related to the ratio of the areas under diastolic and
systolic pressure.
The supply-to-demand ratio depends on the duration
of diastole with respect to the heart period, i.e., the diastolic time fraction. This time fraction has recently received attention (82, 123, 129, 295, 412). The supply-todemand ratio also depends on the ratio of systolic and
diastolic pressure, which decreases with age (448) and
exercise (114), and can give information about (pharmacological) interventions (207, 208).
The supply-to-demand ratio is determined by crosstalk because tissue perfusion in systole depends on cardiac muscle contraction.
C. Summary
Autoregulation of flow is an integrated and coordinated control by an apparently redundant system based
on three interacting mechanisms: myogenic control, metabolic control, and endothelium-based control. The gain
of autoregulation can be quantified. Autoregulation modulates the mechanics of the vasculature and thus affects
mechanical cross-talk. The supply of oxygen mainly depends on diastolic flow, and thus on the diastolic time
fraction. However, even a small flow in systole, e.g., at
high heart rates, can contribute to perfusion and is affected by cardiac contraction. Thus the supply-to-demand
ratio depends on mechanical cross-talk. Quantification of
a stenosis is often based on CFR and FFR. However, CFR
depends on the microcirculation as well, and thus on the
effect of cardiac muscle contraction. The FFR assumes
that the bed distal of the stenosis and the normal representative bed are similarly influenced by cardiac muscle
contraction. Therefore, both CFR and FFR are affected by
cross-talk.
9. Supply-to-demand ratio
Oxygen delivery to the cardiac muscle should be in
equilibrium with the oxygen use or demand. Supply is
related to arterial inflow because coronary oxygen extraction is close to its maximal value. If it is assumed that the
effect of cardiac contraction on the subendocardial layers
is such that coronary perfusion is negligible in systole,
arterial inflow only takes place in diastole. The supply
then can be calculated as the area under the perfusion
pressure in diastole. When there is no stenosis present,
this equals the area under the diastolic aortic pressure.
Thus, under these assumptions, diastolic pressure and the
duration of diastole are the determinants of oxygen supply. Oxygen demand mainly depends on ventricular wall
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III. THE CARDIAC MUSCLE AFFECTS THE
CORONARY VASCULATURE
In this section we discuss the global findings on
coronary pressure-flow relationships of the coronary vasculature in diastole and in systole.
A. Cardiac Muscle and Coronary Flow in Diastole
1. Instantaneous pressure-flow relationship
and zero-flow pressure intercept
A vascular bed, in our case the coronary system, can
be characterized in terms of steady-state and instanta-
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with Pd being the pressure distal of the stenosis and Pprox
the proximal or, in practice, aortic pressure during maximal dilation. The Rst and Rn are the resistances of the
stenosed and normal distal beds during maximal vasodilation. With the assumption that the microvascular bed of
the stenosed area and the normal area have the same
minimal resistance, and with the assumption that venous
or intercept pressure (Pv) (see below) is small with respect to Pd, it holds that the FFR is close to the ratio
Pd/Pprox (275, 320, 361). Keeping these limiting assumptions in mind, the FFR is then an index of lesion severity
only, not including the effect of the microcirculation (96,
226). It has been agreed that for values ⬍0.75 (88, 226),
the stenosis is functionally significant. For a segmented
stenosis, the approach is more complicated.
The main advantage of the FFR is that it can be
derived from flow measurements only that can be carried
out noninvasively using ultrasound Doppler or MRI. The
measurement of distal pressure would obviate a flow
measurement but may, even using a thin pressure wire,
increase apparent stenosis severity.
The relationship between flow velocity and the pressure drop over a stenosis is an accurate and direct quantification of the functional properties of the stenosis, but
more difficult to obtain because measurement of proximal and distal pressures, together with flow, is required
(26, 280, 361).
It has not been established whether the maximal flow
in muscle areas distal of a stenosis is similar to maximal
flow in a normal area. Furthermore, it is not known
whether the effect of cardiac contraction on the coronary
vasculature is similar in these two areas.
When the CFR and FFR are studied in diastole, the
microcirculation is studied without the confounding effect of the cardiac contraction (see below) (120, 248), and
cross-talk will be minimal.
Flow during maximal dilation is, in part, determined
by cardiac contraction, and FFR may thus depend on
cross-talk.
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
FIG. 5. The instantaneous relationship between pressure and flow
can be obtained from a (long) diastole and characterizes the coronary
vasculature without the confounding effect of cardiac muscle contraction and during an assumed constant vasomotor tone. [Adapted from
Bellamy (36).]
FIG. 6. The autoregulation curve is shown together with instantaneous pressure-flow relationships. The instantaneous relationships define the vasoactive state of the coronary vasculature. At lower perfusion
pressure, the slope increases (smaller resistance, Ri), and as a result of
vasodilation, the intercept pressure also decreases. [Adapted from Dole
and Bishop (107).]
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depend on the vasoactive state of the coronary bed. For
increased perfusion pressure, the vasculature constricts
as a result of autoregulation, and the resistance and intercept of the instantaneous pressure-flow relation increase, thereby keeping mean flow in the steady-state
constant (107, 238). In humans, the zero-flow pressure
intercept of the instantaneous pressure-flow relation is
⬃40 mmHg in control and ⬃15 mmHg in vasodilation
(307). A Pf⫽0 is not only found in the left heart but also in
the right heart in diastole (430). These intercept pressures
are significantly higher than coronary sinus pressure, left
ventricular end-diastolic pressure, and right atrial pressure.
The mechanisms causing the zero-flow pressure intercept are still poorly understood. The instantaneous
pressure-flow relationships with the zero-flow pressure
intercept have been likened to a waterfall mechanism, i.e.,
increases in venous pressure do not affect flow as long as
this pressure is lower than the waterfall pressure (Fig. 7).
The intercept pressure depends on vasomotor tone, suggesting that it arises from the smooth muscle in the arteriolar wall. That the intercept is based on vascular properties is also based on the fact that it exists in many beds,
including the whole systemic circulation (57).
Spaan (375, 376) has suggested that the large compliance found in the microcirculation [⬃0.07 ml · mmHg⫺1 ·
100 g tissue⫺1 (375, 376) to ⬃0.38 ml · mmHg⫺1 · 100 g
tissue⫺1 (380)], depending on heart rate (91, 92) and
vasoactive state (423), may explain the intercept. An intravascular volume of ⬃12 ml/100 g muscle has been
reported (196, 411). This large microcirculatory compliance indeed appears to be present, because venous outflow, from blood stored in the microvascular reservoir
(compliance), persists after a sudden stop of arterial inflow (80, 201, 347). After arterial inflow is resumed in a
stepwise manner, venous outflow is delayed, suggesting
an unstressed vascular volume or large compliance, estimated to be ⬃4 ml/100 g muscle (407).
Several authors (142, 201) showed, in the in situ dog
heart during maximal vasodilation, evidence for the existence of a microvascular unstressed volume, which re-
FIG. 7. The principle of a waterfall. Venous pressure does not
determine the flow when it is below the waterfall pressure. It is the
proximal arterial minus the distal waterfall pressure that determines the
flow. When the arterial pressure falls below the waterfall pressure, the
flow stops.
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neous pressure-flow relationships (36, 37, 50). The steadystate relationship is the one that is measured after regulation has taken place (see autoregulation curve of Fig. 2).
The instantaneous relationship is determined over a short
time period (⬃1 s), and the vasculature is assumed to be
in a “fixed” vasoactive state (106, 416). The instantaneous
relationship between pressure and flow of the coronary
circulation can be determined during a long diastole (e.g.,
obtained through vagal stimulation) so that the coronary
vasculature is characterized without the confounding effect of cardiac muscle contraction, i.e., with minimal mechanical cross-talk (Fig. 5). The instantaneous pressureflow relationship, therefore, describes the momentary
state of the vascular bed. Figure 6 shows the steady state,
or autoregulation curve, together with instantaneous
pressure-flow relationships as determined from a range of
steady-state pressures (36). The instantaneous relationships in general appear to be straight (36) or curvilinear
(237, 238) with a so-called zero-flow pressure intercept,
Pf⫽0, i.e., with negligible flow, pressure is still present.
The inverse of the slope of the instantaneous pressureflow relationship is the instantaneous resistance (Ri). The
instantaneous resistance and the intercept pressure both
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WESTERHOF ET AL.
Versluis et al. (424) showed, in isolated perfused rat
papillary muscle, that the waterfall is located in arterioles
larger than 110 ␮m.
It has still not been proven beyond doubt that the
intercept is a real intercept and not an apparent intercept,
i.e., an intercept obtained by extrapolation of the data.
Kanatsuka et al. (210) analyzed in detail the momentary
value of the diameter of arterioles in the coronary bed
while pressure was decreasing. It was found that the
diameters of arterial microvessels gradually decline as
aortic pressure falls. This suggests that the coronary resistance does not remain constant during a long diastole,
even when the bed is maximally dilated (210). The finding
that even during maximal vasodilation a zero-flow pressure intercept is present suggests that a venous waterfall
may exist. A distal, venous, waterfall was indeed shown to
exist in the epicardial coronary veins (409), and also in
the skeletal muscle veins (51). Such a separate venous
waterfall can be seen and studied by cannulation of the
venous system (409). Increased coronary sinus pressure
was shown to decrease flow, but this was less than the
decrease in perfusion pressure (arterial minus venous
pressure), suggesting a waterfall mechanism (303). A
large coronary venous compliance may also explain this
waterfall.
The instantaneous pressure-flow relationship should
be considered with caution. It has been shown that the
relationship may not be linear (238). The relationships
may include a contribution of arterial compliance, because the flow that fills the arterial compliance depends
on the rate of change of perfusion. Thus, when the pressure and flow change occur too rapidly, errors result.
These errors and suggestions for correction have been
reported (24, 61, 237, 282, 283).
Instantaneous pressure-flow relationships are determined over such a short period of time that they describe
the bed in a particular state at the working point. It may
therefore be suggested that the ratio of the slopes of the
autoregulation curve and the slope of the instantaneous
pressure-flow relationship, the regulatory index, are a
better measure of gain of autoregulation than the formula
given in the section on autoregulation gain (416).
2. Summary
FIG. 8. A possible explanation for the apparent intercept. The
“plateau” of the pressure-area relationship relates to the apparent intercept. An increase in vasomotor tone increases the plateau of the pressure-area relationship together with the apparent zero-flow pressure
intercept. [Adapted from Sipkema and Westerhof (364).]
Physiol Rev • VOL
The instantaneous pressure-flow relationships are
determined in diastole and so rapidly that vasomotor tone
may be assumed constant. The relationships describe the
coronary vasculature in “fixed state” of the vasculature
and without the confounding effects of the cardiac muscle
and are therefore not affected by mechanical cross-talk.
The slope and intercept of the relationships both depend
on smooth muscle tone. The intercept is most likely the
result of a large microvascular compliance.
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sults in delayed venous outflow after sudden resumption
of stopped arterial inflow. The filling of the intramyocardial compartment above its unstressed volume affects the
diastolic pressure-flow relationships (142), but not their
intercept, indicating that arterial inflow depends on the
compliance in the microcirculation. In cardiac arrest, the
blood stored in the microcirculation is discharged to the
venous side keeping venules open while arterioles decrease in size (167).
Sipkema and Westerhof (364) showed that the apparent intercept of the pressure-flow relationship of a thinwalled latex microtube (Fig. 8) depends on the plateau of
its pressure-cross-sectional area relationship, which, in
turn, depends on vasomotor tone. Both explanations as
given by Spaan and Sipkema support the hypothesis that
(microvascular) compliance plays a major role in the
explanation of the zero-flow pressure intercept (364, 375,
376). An additional suggestion that the intercept is related
to vessel wall properties is that when the coronary perfusion fluid is changed from blood to a crystalloid medium, an intercept pressure remains (342, 415). However,
others have shown that the perfusion medium does affect
the intercept, suggesting that the rheological properties of
blood may play a role as well (205, 352). It has also been
suggested that surface tension between blood and vessel
wall (358, 359) and the glycocalyx (84, 325, 425) might
contribute to the intercept pressure.
The zero-flow pressure intercept is related to intramyocardial pressure, but the relation is complex (348).
If the heart is subjected to both luminal and external
pressures, using an airtight chamber, the zero-flow pressure of the diastolic pressure-flow relationship is affected
but the slope of the relationship is not (24). This suggests
that intramyocardial pressure can contribute to the pressure-flow relationship. However, the effect is small since
in diastole left ventricular and intramyocardial pressures
are lower than the intercept pressure (297).
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
3. Effect of ventricular volume changes on coronary
flow in diastole
pressure of 70 mmHg, shows changes in microvascular
resistance, calculated on the basis of a model, of about a
factor of 2 (87, 380). However, this study applied stretch
starting from short lengths, namely, “slack length.” Model
calculations predict that when muscle length increases
from ⬃70 to 90% of Lmax, corresponding to a ventricular
lumen volume increase by a factor of 2, diastolic flow is
decreased by ⬃30% (426).
When the pressure-area relationship of an isolated
vessel and the pressure-area relationship of the muscle
cavity in which the vessel fits are added, the pressure-area
relationship of the vessel embedded in muscle is obtained
(159, 427). It was shown that increased diastolic chamber
stiffness does affect coronary vascular compliance (435).
In diastole, the cardiac muscle contributes little to the
pressure-area relationship of an embedded arteriole,
while the pressure-area relationship of an embedded vein
is almost entirely determined by the surrounding muscle
(Fig. 10). Because the small arteries and the arterioles,
but not the venules, mainly determine coronary resistance, the diastolic cardiac muscle influences coronary
resistance only marginally.
The chosen condition of maximal vasodilation reduces the effect of the smooth muscle (see Fig. 6, where
smooth muscle tone affects both slope, i.e., resistance,
and intercept) on the pressure-flow relationships. Thus,
from these studies with maximal vasodilation and in diastolic arrest, it may be assumed that a venous waterfall,
which is reported to exist in epicardial veins, plays a role
(117, 409, 434, 436).
In the dilated heart in diastole, with increased cardiac muscle stiffness and higher diastolic ventricular
pressure, the cardiac muscle has a larger effect on the
embedded arteries and arterioles. Thus, in the dilated
heart, and with most flow taking place in diastole, vasodilatory capacity of the coronary circulation is reduced
and flow reserve is decreased (59).
4. Summary
FIG. 9. Coronary pressure-flow relationships measured in the isolated maximally vasodilated heart in diastolic arrest are only slightly
affected by left ventricular volume. The two filling pressures relate to a
volume increase of about two times. [Adapted from Sipkema et al.
(362).]
Physiol Rev • VOL
The data in the literature regarding the contribution
of the diastolic cardiac muscle on the coronary vasculature are not consistent. Some publications report a small
effect on resistance vessels, while others show a substantial effect. The differences may, in part, result from differences in initial cardiac muscle length and amount of
stretch. However, it appears that if there is an effect it is
stronger on the intercept than on the slope of the pressure-flow relationships. A model accounting for vessels
embedded in cardiac muscle predicts little effect on arterioles but a strong effect on venules. The pericardium, and
therefore the venous waterfall, may also account for part
of the differences reported. However, reconsideration of
the models and more experiments under well-defined
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Several groups have reported diastolic pressure-flow
relationships during maximal vasodilation. Figure 9
shows a representative example of coronary pressureflow relationships in the isolated maximally vasodilated
rabbit heart in diastolic arrest for two filling pressures,
corresponding to a ventricular volume change of about a
factor of 2 (362). The effect is only slightly dependent on
the muscle layer, i.e., subendocardial or subepicardial
(264). In the open-chest dog, an increase in left ventricular
volume from 20 to 50 ml (diastolic left ventricular pressure from ⬃5 to ⬃20 mmHg) did not significantly affect
diastolic coronary arterial inflow (132, 134). However,
when volume was increased to 60 ml (diastolic left ventricular pressure of ⬃28 mmHg), flow decreased by ⬃16%.
In other studies using the isolated dog heart (436) or the
in situ dog heart (119), the pressure-flow relationships in
diastole show a change in the intercept but little change in
slope with ventricular volume changes. After pericardiectomy, the effect of ventricular filling on the relationships
is decreased possibly explaining the differences between
the in situ (117, 119) and isolated heart (362). Aldea et al.
(5) studied the effects of changes in ventricular lumen
pressure and extraventricular pressure on coronary flow
in diastolic arrest. They found an almost parallel shift to
higher intercept pressures of the coronary pressure-flow
relationships, when either lumen pressure or external
pressure was increased. However, they also found an
increase in venous pressure.
Studies on the isolated perfused papillary muscle
show that muscle length has little effect on coronary flow
in diastole (9). Monoaxial and biaxial stretching of the
isolated perfused and maximally dilated interventricular
septum of the dog was reported to result in an increase in
intercept pressure and resistance (333). Biaxial stretching
of this preparation from slack to ⬃20%, at a perfusion
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WESTERHOF ET AL.
1. Arterial inflow and venous outflow
conditions are necessary. In the dilated heart, maximal
flow and therefore CFR is limited.
B. Cardiac Contraction and Coronary Flow
in Systole
The coronary arterial inflow is impeded and venous
outflow is augmented during cardiac muscle contraction.
In contraction the total vascular volume is decreased,
which means that the resistance of the vasculature is
increased. The cardiac muscle is also stiffer so that compliance of the embedded vasculature is decreased, also
resulting in a decrease in vascular volume. The vascular
volume decrease causes blood to be pumped out. This
results in the arterial inflow impediment and venous outflow augmentation. Here we discuss these phenomena as
an introduction to the models reported in the literature.
Physiol Rev • VOL
FIG. 11. Systolic coronary flow impediment. Coronary flow decreases in systole and may even reverse. [Adapted from Gregg and
Green (153).]
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FIG. 10. Top: schematic presentation of an isolated vessel (left) and
a vessel embedded in muscle (right). Middle: diastolic pressure-area
relationships of an isolated arteriole (left) and an isolated venule (right)
and of the muscle cavity in which they are embedded (thin lines).
Bottom: pressure-area relationships of the vessels surrounded by muscle. The dashed lines are the pressure-area relationships of the vessel
alone, given for comparison with the middle panels. [Adapted from Vis
et al. (427).]
Anrep and co-workers (12, 13) and Gregg and coworkers (153–156) have already shown that coronary arterial inflow is impeded and venous outflow is augmented
during cardiac contraction. When the coronary bed is
vasodilated and cardiac muscle contractility is high, arterial inflow may even reverse in early systole (see Fig. 11).
This so-called systolic arterial flow impediment has been
confirmed by many research groups in isolated heart studies (48, 175, 245–249) and in the in situ heart (5, 73, 111,
115, 128, 152, 154, 175, 197, 200, 267, 412), and it has been
observed in humans as well (26, 128, 198, 278, 286). It is
also observed in the circumflex coronary artery in control
and in increased cardiac contractility (200) and has been
seen in septal coronary artery stenosis (141, 204, 227).
Coronary mean pressure-mean flow relationships measured in the heart in situ during maximal vasodilation
show that mean flow decreases with exercise as a result
of the decreased duration of diastole. This finding emphasizes that the major contribution to mean flow is during
diastole and that systolic flow is small (115). Increased
venous outflow in systole is found in the great cardiac
vein, and the magnitude is greater with increased contractility [202; see for discussion also the publications by
Olson and Bugni (314), Hoffman and Spaan (175), and
Spaan et al. (378)].
With vasodilation the vascular diameters and vascular volumes increase. This implies a smaller resistance
and larger amount of blood stored in the vasculature.
Thus, in vasodilation, both mean flow and the difference
between diastolic and systolic flow are increased (49).
Many researchers assumed that the cardiac muscle
contraction generates a ventricular lumen pressure that is
communicated to the interstitium, thereby causing an
intramyocardial pressure (20, 111). The increased intramyocardial pressure subsequently causes a decrease in
the transmural vascular pressure and thus a decrease in
vascular diameter. The decrease in vascular diameters in
systole causes a decrease in vascular volume, and this
volume is “pumped” to venous and arterial sides of the
coronary circulation. The diameter decrease also causes
an increase in coronary resistance. However, there is not
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
The impulse response has subsequently been used to
derive input impedance [for details about the calculation,
see Sipkema et al. (366)]. The input impedance of the
coronary bed in systole and diastole is shown in the right
panels of Figure 12B. It may be seen that only the 0-Hz
term and low frequencies of the input impedance are
affected by cardiac contraction, while the higher harmonics of the input impedance are not affected by cardiac
contraction. This result is confirmed by the work of Cornelissen et al. (87) and Spaan et al. (380) who showed, by
analyzing their experimental data using a lumped model
of the coronary circulation, that cardiac muscle contraction exerts its main effects on the proximal part of the
microcirculation (their resistance 1).
3. Summary
2. Coronary arterial input impedance
The decrease in coronary arterial inflow in systole is
based on changes in the coronary vascular system. The
changes in the arterial part of the circulation can be
studied by the derivation of arterial input impedance,
which is a comprehensive description of the entire coronary arterial system. While peripheral resistance mainly
characterizes the peripheral vasculature, the input impedance gives a description including both the proximal part
of the vasculature, the arterial conduit vessels, and the
periphery (448). Input impedance cannot be determined
in the standard way by applying Fourier analysis on the
pressure and flow signals, because during a heart beat the
contracting cardiac muscle affects the system, i.e., we are
studying a time-varying system (448). Therefore, the socalled impulse response method has been applied in systole and diastole (266, 366, 417). It was shown that the
response is rather short in duration so that it can be
determined in systole and diastole separately. In the left
panels of Figure 12A, the impulse responses are shown,
superimposed on the pressure waveform. By subtracting
the waveform without impulse response from the one
containing the impulse response, the response alone is
calculated.
As a result of cardiac contraction, flow in large arteries is impeded in systole and flow in large veins is augmented in systole. The magnitude of coronary arterial
flow impediment depends on perfusion pressure and cardiac muscle contractility. Venous outflow depends on
cardiac contractility and venous pressure.
Two mechanisms exist to explain the findings. First,
cardiac contraction causes, via the generation of ventricular pressure, an intramyocardial pressure. This decreases vascular transmural pressure and vascular diameter and volume and increases resistance. Second, cardiac contraction results in changes in the muscle
properties such as stiffness, and the muscle length and
thickness vary over the cardiac cycle. These phenomena
directly affect the vasculature. The cardiac muscle contraction results in vascular volume and resistance
changes, which mainly take place in the microcirculation.
C. Models Explaining the Diastolic-Systolic
Changes of the Vasculature
The contracting cardiac muscle exerts an impeding
effect on arterial inflow and augments venous outflow.
FIG. 12. A: the impulse response of the
coronary bed. A short impulse (a few milliseconds) of flow results in a pressure response as a function of time (top panel).
This pressure is superimposed on the pressure resulting from cardiac contraction
(dotted line). When this latter pressure is
subtracted, the pure impulse response is obtained (bottom panel). B: the coronary arterial input impedance derived from the impulse response. The differences between diastole and systole are only present in the
mean term, implying that the effect of cardiac contraction is mainly present in the
periphery. [Adapted from Van Huis et al.
(417).]
Physiol Rev • VOL
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only an effect of intramyocardial pressure on the vasculature but also a direct contribution of the cardiac muscle
on the vasculature. The cardiac muscle becomes stiffer in
systole; it may shorten and thicken leading to a decrease
in vascular diameters and volume. Shortening of the cardiac muscle cells will also deform the vasculature (change
branching angles at bifurcations and increase vascular
tortuosity). The two mechanisms, the indirect effect
through ventricular pressure and the direct effects of the
cardiac muscle, both play a role depending on the conditions. For example, the contribution of ventricular pressure depends on the elastance of the ventricular wall, i.e.,
in systole, when the ventricular muscle is stiff, the effect
of ventricular pressure is shielded off by muscle stiffness
(243). The concepts and models are discussed below.
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WESTERHOF ET AL.
isovolumic), and the layer in the heart wall (subepicardial,
subendocardial).
1. The waterfall model
The first well-described and accepted model to explain coronary arterial inflow impediment in systole is
based on the “vascular” waterfall (111) (Fig. 7). As mentioned above, the vasculature alone exhibits a zero-flow
pressure intercept, which is a vascular waterfall dependent on smooth muscle tone but independent of the surrounding (cardiac) muscle. In this section we discuss the
waterfall that results from cardiac muscle contraction.
We therefore prefer the term waterfall model instead of
the term vascular waterfall model as is most often used in
the literature. Farhi et al. (122) elegantly showed that in
ventricular fibrillation a cardiac muscle- and smooth muscle-based waterfall exists and that vasodilation could
lower the waterfall pressure. The main aspect of the
waterfall model is that the flow is not determined by the
arterial minus venous pressure and vascular resistance,
but by arterial minus waterfall pressure and vascular
resistance (51, 122). This means that calculations of resistance, by dividing the arteriovenous pressure difference by flow (or since venous pressure is much lower
than arterial pressure, simply arterial pressure divided by
flow) are not correct (see sect. IIB5).
The waterfall model as proposed by Downey and
Kirk (111) states that ventricular pressure generates a
so-called intramyocardial or interstitial pressure Pim,
which acts on the outer surface of the blood vessels (Fig.
13A, left). This intramyocardial pressure is transmitted to
the vascular lumen and forms the basis of the waterfall
pressure. The intramyocardial pressure is assumed to be
equal to ventricular pressure Plv at the subendocardium,
and negligible at the subepicardium (111): Pim ⫽ k⫻Plv,
with k ⫽ 1 at the subendocardium and k ⫽ 0 at the
subepicardium. The intramyocardial pressure is largest in
FIG. 13. The waterfall model. A: the intramyocardial pressure or interstitial pressure, here presented as external pressure to the vessel, causes
a (partial) collapse, and this distal intravascular pressure is close to the external or intramyocardial pressure. Intramyocardial pressure is assumed
to result from ventricular lumen pressure and equals that pressure in the subendocardial layers of the heart wall, and is decreasing to negligible
values at the subepicardial side of the wall. The electrical representation of the model (A, right) contains a one-way valve, given by the diode, to
prevent flow from interstitium to vessel lumen. The electrical model therefore does not allow for an increase in venous outflow during an increase
in Pim due to cardiac contraction. B: predicted pressure-(in)flow relationships. Part, Pim, and kPlv are arterial, intramyocardial, and ventricular
pressure, respectively. Pv is venous pressure, and the zero-flow intercept pressure is Pd ⫽ Pim. R is vascular resistance. [Adapted from Downey and
Kirk (111).]
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The coronary arterial input impedance data show that this
effect of contraction on coronary flow mainly results from
changes in the vasculature.
The effect of cardiac muscle contraction on the coronary vasculature is based on two mechanisms.
The cardiac muscle contraction increases ventricular
lumen pressure, which results in an increase in interstitial
or intramyocardial pressure. This pressure is proportional
to ventricular pressure and decreases the vascular transmural pressure, and thereby vessel diameter. This concept forms the basis of the waterfall model (111), and the
intramyocardial pump model (19, 379). Experiments have
shown that pressure, applied in the lumen of the ventricle
and externally by means of a pressure chamber (5) or
through the pericardium (395), has an effect on coronary
pressure-flow relationships.
The contraction of the cardiac muscle causes a decrease in vascular diameters and deformation of the blood
vessels by a direct effect. This concept is formulated by
the varying elastance model. An increase in stiffness of
the cardiac muscle (vessel environment) decreases vessel
lumen similar to what happens in the ventricular lumen
during contraction (245, 387, 447); in the muscle shortening and thickening model, the shortening and related
thickening of the muscle fibers during contraction cause a
decrease in vessel diameters (426, 450); and in the vascular deformation model, deformation of the vasculature,
vessel shortening, changes in bifurcation angles, and
changes in tortuosity result from muscle contraction (169).
Contractility has an effect on coronary pressure-flow
relationships independent of ventricular lumen pressure
(247, 420).
It turns out that neither of these concepts, alone,
completely describes what happens to the coronary vasculature during cardiac muscle contraction. Also the contribution of their effects depends on the contractile state
of the heart, the mode of cardiac contraction (isobaric,
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
FIG. 14. The intramyocardial pump model. This model improves the
waterfall model. The intramyocardial pump model mimics the decrease
in arterial inflow and increased venous outflow in systole and allows for
reversal of arterial inflow. The capacitor in the electrical analog implies
that during maintained contraction, “heart arrested in systole,” flow is
not different from arrest in diastole. Symbols are as in Figure 13.
[Adapted from Spaan et al. (378).]
in systole is accounted for (Fig. 14). However, the compliance in the model prevents changes in mean flow between the heart arrested in diastole and systole. The
electrical representation of the model contains a capacitor, implying this same limitation in static conditions. The
model has been extended to include the changes in flow in
the steady state of contraction, by making the resistances
dependent on intramyocardial pressure (53, 376). Several
lumped and distributed models have been based on the
intramyocardial pump concept (19, 20, 42, 58, 66, 369 –
371, 461, 462). The modified intramyocardial pump model
(53, 175, 376) does include changes in vascular volume
and resistance but does not include vascular compliance
changes.
3. The varying elastance model
The assumption that left ventricular pressure is an
accurate predictor of coronary arterial flow impediment
was challenged by the experiments in the isolated bloodperfused cat heart as shown in Figure 15 (249). Similar
results were observed in the in situ dog heart (420). When
contractility of the heart is maintained constant while the
ventricular load is changed in such a way that the ventricle contracts isovolumically (i.e., nonejecting contraction) or isobarically (i.e., contractions without pressure
generation in the ventricular lumen), coronary arterial
inflow is similarly affected. Thus, while ventricular pressure is changed, but aortic and coronary sinus pressures
are kept constant, the effect of cardiac muscle contraction on coronary flow is similar. This led to the hypothesis
that it is the variation in stiffness of the cardiac muscle
during the cardiac cycle that is the cause of the flow
impediment (245–247).
The increasing stiffness of the muscle in systole affects the vascular volume and the lumen of the ventricle
similarly, as exemplified in Figure 16. The formulation is
based on the varying elastance concept as introduced by
Suga et al. (387). The varying properties of the cardiac
2. The intramyocardial pump model
Spaan et al. (376, 378, 379) introduced the intramyocardial pump model, originally suggested by Arts and
Reneman (19, 20), which is based on the pumping action
of the cardiac muscle in analogy to the ventricular pump.
The intramyocardial pump model improved the waterfall
model such that reversal of arterial inflow in systole (Fig.
11) can be explained and the increase in venous outflow
Physiol Rev • VOL
FIG. 15. Coronary flow during isovolumic beats (left, no ejection)
and isobaric contractions (right, no pressure development) is similarly
impeded in systole. [Adapted from Krams et al. (247).]
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subendocardial layers, and thus the effect of contraction
is strongest there. This model explains that with decreased perfusion pressure, as distal to a stenosis, ischemia is mostly subendocardial.
The electrical representation of this model is given in
Figure 13A, right. The diode in the electrical analog was
introduced to prevent blood being pumped from the interstitium into the vascular system. However, the anatomical equivalent of the diode is missing, and it does not
allow for negative arterial inflow in systole. Another limitation of the (electrical representation of the) model is
that venous outflow does not increase in systole. The
waterfall model assumes that the resistance is not affected by cardiac contraction and that the waterfall is
located distally from the resistance. The model predicts
coronary flow reduction in systolic cardiac arrest. This
flow is only close to systolic flow in the beating heart,
when also ventricular pressure has a systolic value. When
in systolic arrest ventricular pressure is low, flow is not
impeded, in contrast to what has been observed experimentally (362). The intramyocardial pressure effect is
supported by the finding that the zero-flow pressure intercept of the coronary pressure-flow relationships is increased when lumen pressure and external pressure are
increased together in the heart arrested in diastole (5).
However, the zero-flow pressure intercept is little affected
by an increase in pericardial pressure (260), apparently
contradicting the waterfall model. The waterfall model
does not account for changes in vascular resistance and
volume.
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WESTERHOF ET AL.
muscle during contraction cause an increase in the slope
[the elastance, E(t)] of the pressure-volume relationships
of the ventricular, interstitial, and vascular compartments. When cardiac contractility is increased, the magnitude of the E(t) curve also increases, and the vascular
volume decreases. The greater decrease in vascular volume causes a larger decrease in coronary arterial inflow
(247) and a greater increase in venous outflow in systole.
More exactly formulated, the rate of change of vascular
volume determines the sum of the decrease in arterial
flow and the increase of venous outflow. Baan et al. (25)
and Van Winkle et al. (420) confirmed the major effect of
ventricular elastance on flow impediment in the dog heart
in situ. The varying elastance model implies that all arteries, capillaries, and veins are subject to the variations in
cardiac muscle stiffness during contraction. Thus the suggestion implied in the waterfall model and intramyocardial pump model that cardiac contraction has its effect on
the microcirculation only is not assumed in the varying
elastance model. This model also abandons the idea that
the effect of contraction acts via ventricular lumen pressure. The model explains that there are differences in
pressure-flow relationships between diastole and systole
not only in the beating heart but also in the arrested heart,
in isolated perfused papillary muscle (9, 263), and in
skeletal muscle.
Calculations based on the varying elastance hypothesis have been carried out by Vis and co-workers (426 –
429). When an artery is embedded in muscle, the pressurePhysiol Rev • VOL
volume relationship depends on the vascular wall properties and on the (varying) elastic properties of the
surrounding myocardium. This means that both the elastic properties of the vessel wall and of the cardiac muscle
in which the vessel is embedded contribute to the pressure-diameter relationship (Fig. 17). While for an artery in
diastole its wall properties mainly determine resistance
and compliance, in systole the role of the cardiac muscle
properties is considerable. For a venule, the pressurediameter relationship is almost entirely determined by the
surrounding muscle, both in diastole and in systole. Thus,
in systole, with increased stiffness of the cardiac muscle,
the muscle contributes to the pressure-diameter relationship of the vein as well as the artery. When changes in
diameter due to cardiac contraction are calculated, the
cross-sectional area of the arteriole decreases by ⬃50%
(at a distending pressure of ⬃40 mmHg) and that of the
venule by ⬃40% (at a distending pressure of ⬃7 mmHg),
both at their working pressure level (Fig. 17). Thus
venules are not being compressed (collapsed) completely
as would be expected when intramyocardial pressure is
close to ventricular pressure in the subendocardial layers.
These calculations are based on vessels embedded in
isolated cardiac tissue where, in contrast to the wall in the
intact heart, ventricular pressure is not present.
The varying elastance model accounts for vascular
volume, resistance, and compliance changes. The model
holds for shortening and muscle-isometric contractions,
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FIG. 16. The varying elastance model. The ventricular lumen and vascular volume are both subject to the
time-varying properties of the cardiac muscle. In the top
two panels, the ventricular pressure-volume trajectories, dashed arrows, are shown during an isovolumic
contraction (left) and an isobaric contraction (right). In
the bottom two panels, the corresponding pressure-volume trajectories of the vascular volume (dashed arrows) are shown. These vascular trajectories are the
same when contractility is maintained, because the perfusion pressure and venous pressure (loading conditions of the vasculature) are the same. When the load on
the heart is changed, the effect on the vasculature remains the same.
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
although the latter conditions, in practice, are nonexistent.
4. The muscle shortening and thickening model
Muscle shortening also affects the vasculature since
during contraction muscle cell volume is constant and
muscle shortening implies an increase in muscle diameter. The increase in muscle diameter partly takes place at
the expense of the vessels, thereby decreasing their diameters as shown in Figure 18 (450). This effect is not
present in muscle-cell isometric contractions, because
when the muscle length does not change, the diameter
does not change either. The effects of changes in muscle
length on the coronary vasculature in diastole have been
discussed above (sect. IIIA3). Quantitative information on
the effect of muscle thickening and shortening during
contraction on coronary flow is lacking.
ies is small (459). However, Pries et al. (324) showed that
the geometry of blood vessels of the microcirculation is a
determinant of resistance. It has been calculated that the
capillaries, that are tethered to the cardiac muscle, also
change in length during contraction (125). Mainly because
deformation is not easily quantifiable and surrounding
muscle structure is very complex (66, 274, 277), quantitative information is lacking. Tortuosity can be indexed by
the ratio of shortest distance and total length of a vessel,
but changes in tortuosity resulting from cardiac contraction have not been quantified either. Tortuosity also
changes with cardiac remodeling (186). Coronary arteries
bend during cardiac contraction (326) and bifurcations
will change in shape (318), causing changes in velocity
distribution and in resistance. McCulloch et al. (290) have
reported on the complex relationship between circumferential, longitudinal, radial fiber strains, and cross-fiber
strains with local blood flow. They have shown that the
relationship between flow and systolic strain depends on
segment orientation. In the low pressure left atrium, the
velocities in the small arteries and veins are related to
ventricular contraction (203), arguing in favor of the vascular deformation model. Deformation of the transmurally penetrating vessels is particularly complex (168,
169). This is in part due to the effect of shearing forces,
and at present, no good model exists. Figure 19 shows the
importance of the transmural vessels in the beating heart
(72). The perfusion pressure, when expressed as arterial
minus venous pressure, is at the subendocardium only
about half of that at the subepicardium (70). This means
that a decrease in perfusion pressure, such as distal of a
stenosis, affects the subendocardial perfusion more than
subepicardial perfusion (296). This pressure drop over the
transmural vessels may be an alternative or a complementary explanation for the fact that subendocardial layers
are more prone to ischemia than subepicardial layers
5. The vascular deformation model
The effect of contraction on the deformation of the
vasculature (changes in shape of the vascular cross-sections, branching angles, and vessel tortuosity) has received little attention. The effect in large coronary arterPhysiol Rev • VOL
FIG. 18. The muscle shortening and thickening model. During muscle contraction and shortening, the muscles increase in diameter at the
expense of the coronary vasculature. Purely muscle-isometric contractions would not affect the coronary flow.
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FIG. 17. Blood vessels are embedded in muscle. When the cardiac
muscle contracts, and becomes stiffer, the surroundings play a larger
role. These model calculations show that an isolated arteriole has a
pressure-area relationship given by the thick solid line (top, left), while
the cavity in the cardiac muscle has a pressure-area relationship in
diastole, thin line and systole, dashed line. When the arteriole is embedded in the muscle (bottom, left), the thick line gives the diastolic relationship, and the dotted line gives the systolic relationship. For a constant intravascular pressure of 40 mmHg, the diameter of the arteriole
changes by ⬃50% between diastole and systole. The pressure-area relationships of the venule and surrounding muscle are given in the two
right panels. The pressure-diameter relationship of the venule embedded
in the muscle is almost entirely determined by the surrounding muscle,
both in diastole and systole. For a constant intravascular pressure of 7
mmHg, the venular area will change by ⬃40%. [Adapted from Vis et al.
(427).]
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FIG. 19. When perfusion pressure is defined as the arteriolar-venular pressure gradient, it is about half as high in the subendocardial layers
than in the subepicardial layers, thereby showing the importance of the
transmural vasculature. [Adapted from Chilian and DeFily (72).]
6. Summary
Two basic mechanisms have been proposed to explain the effect of cardiac muscle contraction on the
vasculature. The first mechanism is that cardiac contraction through the generation of ventricular lumen pressure
causes an intramyocardial pressure, and intramyocardial
pressure affects vascular transmural pressure. Thus, without ventricular pressure generation, the coronary vasculature is not affected by cardiac muscle contraction (isobaric ventricular contraction and contraction in isolated
papillary muscle). The waterfall model and the intramyocardial pump model are both based on this concept. The
second mechanism explains the effect of contraction by
means of a direct effect of the cardiac muscle on the
vasculature, and the ventricular lumen pressure does not
play a role. The varying elastance model, the muscle
shortening and thickening model, and the vascular deformation model are aspects of this mechanism. These models can explain local effects of contraction and heterogeneity.
Both mechanisms play a role, depending on the layer
in the wall and mode of contraction, and can explain why
subendocardial perfusion is most prone to perfusion limitation in systole.
D. Applications and Limitations of the Models
1. Arterial inflow and venous outflow
In systole, arterial inflow is impeded and venous
outflow augmented. Coronary flow impediment results
from changes in vessel diameter after contraction of the
cardiac muscle. In the small vessels, the diameter variaPhysiol Rev • VOL
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(169). Myocardial ischemia and reperfusion results in a
transmural gradient of dysfunction in radial and crossfiber segments, but not in fiber segments (288). Hoffman
(169) has presented a review of transmural vessels that
are subject to deformation.
tion results in a resistance change (Poiseuille’s law, Ref.
448) and in the larger vessels the diameter change mainly
gives a volume change. Thus the magnitude of the arterial
inflow impediment depends on the rate of change of
vascular volume, the resistance, and the perfusion pressure. If resistance is high, mean flow is small, and the rate
of change of the vascular volume is large (such as during
high cardiac contractility), the volume change produces
reversal of arterial inflow (backflow). Similarly, the rate of
change of the vascular volume and the venous pressure
determine the increase in venous outflow. The lower venous pressure causes most of the volume to move to the
venous side of the coronary circulation.
The waterfall model (111) is based on an intramyocardial pressure Pim that is transmitted to the interstitium
and, subsequently, to the intramyocardial blood vessels
generating a “back pressure” (Fig. 13A). The intramyocardial pressure is assumed to be proportional to ventricular
lumen pressure Plv and decreasing from subendocardium
to subepicardium. The increase in back pressure in systole explains arterial inflow impediment. Thus the relationships between pressure and arterial inflow show a
change in intercept, but no change in slope (resistance)
during cardiac contraction (Fig. 13B). Vascular volume
and vascular resistance changes are not made explicit in
this model. Therefore, the increase in venous outflow and
the reversal of arterial inflow in systole are not represented in the model. When intramyocardial pressure is
higher than arterial pressure, the model implicitly assumes that flow is not reversing but is negligible. This is
made clear in the electrical representation of the model
(Fig. 13A, right), which contains a diode. The diode does
not have a direct hydraulic equivalent but was introduced
to prevent volume from moving from the extravascular to
the intravascular compartments when intramyocardial
pressure is higher than coronary arterial pressure.
The intramyocardial pump model (Fig. 14) (378)
maintained the idea that intramyocardial pressure is proportional to ventricular lumen pressure, but made a conceptual step forward by allowing for arterial flow impediment, inflow reversal, and venous outflow increase in
systole. The vascular compliance is modeled, but constant, and vascular volume changes are modeled by the
changes in intramyocardial pressure (Pim). In the original
publication (378) resistance is not changed during contraction. In a subsequent approach (53) the arterial and
venous resistance were made to change as well.
Since the waterfall model and the intramyocardial
pump model require ventricular pressure as an essential
intermediate step to explain coronary flow impediment,
they do not predict flow impediment during isobaric ventricular contractions (Fig. 15) and in isolated perfused
papillary muscle (9, 263).
The varying elastance model (Figs. 16 and 17) predicts vascular volume changes and thus changes in coro-
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
2. Static versus dynamic systole
The separation of pressure-flow relationships into
diastolic and systolic relationships is difficult to perform.
This difficulty is mainly caused by the fact that not only
pressure and flow are time dependent but that the vasculature varies in time as well. Several investigators have, in
different ways, attempted to separate the coronary pressure-flow relationships into their systolic and diastolic
subparts. For instance, the relation between mean flow
and pressure and the pressure-flow relationship in diastolic arrest can be subtracted to estimate the systolic
pressure-flow relationship (22, 128, 184). On the one hand,
errors may occur because the filling and emptying of the
vascular compartment is not easy to account for in this
subtraction approach, but on the other hand, Bouma et al.
(48) showed that the coronary flow impediment in systole
is mainly the result of resistance changes, rather than
arterial compliance changes. Aldea et al. (5) have reported pressure-flow relationships in systolic arrest in the
in situ heart. Sipkema et al. (362) reported pressure-flow
relationships in the isolated rabbit heart arrested in diastole and in systole (Fig. 20). The data show that pressureflow relationships are different between diastole and systole in the beating heart and in cardiac arrest. Similar
results have been reported on the interventricular septum
Physiol Rev • VOL
FIG. 20. An example of pressure-flow relationships in systole and
diastole in the beating heart and the same heart arrested in systole and
in diastole. [Adapted from Sipkema et al. (362).]
(273). Lamberts et al. (264) showed that pressure-flow
relationships in the subendocardial and subepicardial layers of the isolated rat heart also differ between diastolic
and systolic arrest.
The waterfall model (Fig. 13) predicts differences
between the coronary pressure-flow relationships in the
beating heart as well as in static systole and diastole as
obtained by cardiac arrest. However, the differences in
systolic and diastolic flow in the arrested heart are predicted to take place only if ventricular pressure is high in
the systolic arrest. The intramyocardial pump model, in
its original form (Fig. 14), does not predict differences in
the pressure-flow relationships in the diastolically and
systolically arrested heart (378). However, Spaan and coworkers (243, 376, 380) have improved the intramyocardial pump model to include changes in resistance with
cardiac contraction so that static contraction effects are
predicted.
The varying elastance model applies to both the beating condition and to arrest. In the beating condition, both
the changes in resistance and in vascular volume play a
role, while in arrest only the larger resistance in systole is
contributing. Therefore, the differences between systolic
and diastolic flow are present in both the beating and
arrested heart, but smaller in cardiac arrest.
The muscle shortening and thickening model and the
vascular deformation model both predict that the coronary flow in the heart arrested in systole is smaller than in
diastole, but quantification is missing.
In summary, pressure-flow relationships in the heart
arrested in systole and arrested in diastole show that flow
impediment is present and not only found in the beating
condition. This difference in inflow implies that resistance
is higher because vascular volume is smaller. All models
can account for this except the original version of the
intramyocardial pump model. In the waterfall model, it is
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nary resistance. The varying elastance model also explains the changes in vascular compliance, because the
vessel wall and the cardiac muscle in which the vasculature is embedded determine in situ vascular compliance.
The muscle thickening and shortening model (Fig.
18) predicts changes in vascular volume and thus also in
resistance during cardiac contraction. This model explains arterial inflow impediment and venous flow augmentation. The vascular deformation model is predicted
to mainly change resistance, and therefore, backflow and
venous outflow augmentation are not included in the
model. Neither of these two models has been worked out
quantitatively.
It was shown that cardiac contraction also forms an
important defense against the formation of interstitial
edema (8, 419).
In summary, under physiological conditions, all models contribute to the explanation of coronary arterial inflow impediment. The effect of cardiac contraction based
on the intermediate role of ventricular pressure cannot
explain the flow impediment in isobaric beats (Fig. 15)
and isolated perfused cardiac muscle. The varying elastance model and the muscle shortening and thickening
model, and the vascular deformation model, through their
direct effect on the vasculature, can explain impediment
in isobaric contractions and isolated muscle. The venous
outflow augmentation in systole is not included in the
waterfall model.
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the increase in back pressure rather than resistance increase that explains the impediment. The waterfall model
and the intramyocardial pump model require that in systolic arrest, ventricular pressure is high for flow to be
smaller. In some reports, the difference in pressure-flow
relationships between static and dynamic systole is small,
suggesting that the role of vascular compliance is limited.
However, arterial inflow reversal must result from the
rate of change of vascular volume, implicating vascular
compliance.
3. Coronary arterial input impedance
Physiol Rev • VOL
4. Effect of contraction in layers of the heart wall
In the normal physiological condition, mean flow in
subendocardial and subepicardial layers differs little (176,
237, 249). However, during perfusion in systole only, flow
is smaller in subendocardial layers than in subepicardial
layers (110). The contributions of contractility and aortic
pressure (afterload) were shown to depend on the layer in
the heart wall, and dobutamine decreased systolic subendocardial flow less than subepicardial systolic flow (184).
However, systolic flow was not measured but calculated
from the difference in flow between beating and systolic
arrest. In general, subendocardial flow is more affected by
cardiac muscle contractility than subepicardial layers.
The waterfall and the intramyocardial pump model
explain, by assuming that Pim ⫽ k⫻Plv, with k ⫽ 1 at the
subendocardium and k ⫽ 0 at the subepicardium, that the
effect of contraction is most important in the subendocardial layers. Aldea et al. (5) studied the effects of luminal and external pressure on coronary overall flow and
flow in different layers and showed the importance of
pressure in the wall.
The varying elastance model, under the assumption
that no differences in cardiac muscle properties exist
between subendocardial and subepicardial layers, cannot
explain the different effects of cardiac muscle contraction
in these layers. Although detailed information on cardiac
muscle properties, length, and shortening in different layers has not been reported, these differences may exist.
For instance, a recent study by Neagoe et al. (308) reports
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The changes in coronary arterial input impedance
with cardiac contraction are shown in Figure 12. Other
studies report similar results (60, 194, 195, 445). The
general finding is that the impedance, and parameters
derived from models such as the windkessel model (282,
444, 445, 448), are little affected by contraction except for
the resistance, which is mainly located in the microcirculation. The small effect at low frequencies, where compliance dominates the input impedance (448), suggests that
most compliance is located in the epicardial arteries, and
variation with contraction is small.
Spaan et al. (380) derived, in the isolated perfused
interventricular septum in diastole, the coronary arterial
input impedance (in terms of its inverse, i.e., admittance)
by using sine waves of pressure and flow. They showed,
on the basis of a two-compartment model, that input
impedance depends on perfusion pressure and that volume dependence of the resistances of the model is required to obtain reasonable estimates of intramyocardial
compliance (⬃0.3 ml · mmHg⫺1 · 100 g tissue⫺1).
The waterfall model (111) and the original version of
the intramyocardial pump model (378), where resistances
were assumed to be constant, do not correctly predict the
changes in input impedance, i.e., the change in resistance.
The later version of the intramyocardial pump model
(376), where resistance does change, is in agreement with
the impedance change. The varying elastance model is
supported by the fact that resistance changes are due to
changes in muscle stiffness. The results obtained by wave
intensity analysis also support the varying elastance
model (174, 389, 390). The muscle shortening and thickening model and the vascular deformation model also
predict changes in resistance.
Surprisingly, little attention has been paid to the
analysis of flow waveforms in the coronary circulation. In
the systemic and pulmonary circulation, numerous studies exist that extract important information from the pressure and flow waveforms themselves, as well as by means
of impedance calculation and wave reflection (315, 448).
This type of sophisticated analysis has not yet been developed for the coronary circulation. Sun et al. (389, 390)
used wave-intensity analysis to obtain information on the
effects of cardiac contraction on the coronary system.
These authors were able to separate the effects of contraction in proximal (aortic) and distal (microcirculatory)
(389) and show that coronary systolic flow impediment
depends on contractility (390). Thus wave intensity analysis provides important information (174), but its use is
still limited.
Recently, several clinical groups indicated the importance of the information contained in the flow waveform,
especially its pulsatility, i.e., the difference between maximal diastolic flow and minimal systolic flow, by showing
that in bundle branch block peak flow and acceleration of
flow differ from the normal pattern (367, 368). Also, the
effect of thrombolysis in infarction (454), aortic stenosis
(224), hypertrophic cardiomyopathy (4), and aortic stenosis (456) on the arterial inflow pattern has been reported.
In summary, the varying elastance model, the muscle
shortening and thickening model, and the vascular deformation model explain input impedance better than the
waterfall model and the intramyocardial pump model.
Data on input impedance in diastolically and systolically
arrested hearts are not yet available. Waveform analysis is
virtually lacking in coronary research but could provide
important information.
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
Myocardial bridging (7), where an epicardial coronary artery runs intramurally through the myocardium,
results in compression of the artery in systole and decreased perfusion pressure in systole. Subepicardial intramyocardial pressure is negligible according to the waterfall model and intramyocardial pump model and therefore do not suggest a role of cardiac contraction in
bridging. The varying elastance model, the muscle shortening and thickening model, and the vascular deformation
model can explain the effect of contraction on bridging.
In summary, the waterfall model and intramyocardial
pump model explain the smaller flow in systole in subendocardial layers compared with that in subepicardial layers. This explains the finding that infarcts are most often
found at the subendocardium. The varying elastance
model, the muscle thickening and shortening model, and
the vascular deformation model can explain layer-dependent effects on flow if muscle properties, lengths, or
shortening differ between layers, and when the effect of
contraction on transmural vessels, lowering the subendocardial perfusion gradient, are taken into account. Quantitative comparison between the effects of intramyocardial pressure, differences in muscle properties in different
layers, and the effect on transmural vessels require more
measurements and modeling.
5. Cardiac contraction and the coronary
microcirculation
FIG. 21. Model calculations on the effect of cardiac contraction on
vessel area (top) and resistance (bottom) in subendocardial and subepicardial layers of the heart. E is the effect of elastance, P the effect of
ventricular pressure, and ␭ is the effect of muscle shortening. Isovolumic and isobaric contractions are indicated by iv and ib, respectively. It
can be seen that the contributions of ventricular pressure, elastance
changes, and muscle shortening depend on the type of contraction and
layer in the heart wall. [Adapted from Vis et al. (426).]
Physiol Rev • VOL
A) FLOW AND VELOCITY IN THE MICROCIRCULATION. Blood flow
and blood flow velocity in the coronary microcirculation
during contraction have been reported (21, 79, 81, 199,
206, 230, 231, 406). In subepicardial arterioles and venules
(15–30 ␮m in diameter) and in capillaries, flow velocity
during the isometric contraction phase of the left ventricle decreases strongly and even reverses (Fig. 22). Then,
already during the remaining part of systole, flow increases and subsequently decreases slowly in diastole
due to the decreasing perfusion, or aortic, pressure (Fig.
22A). These data on microvascular velocity in the subepicardium (Fig. 22A) hardly show the reversal of arteriolar
inflow and no augmentation of venular outflow in systole.
Actually, the velocities, in arteriole and venule, are rather
similar in magnitude and wave shape (21). Differences
between subendocardial and subepicardial arterial blood
flow velocities are shown in Figure 22, B and C, and these
patterns show some similarities. In the wall of the left
atrium in systole, flow is impeded in the small arteries and
increased in the veins (203).
These findings suggest that the effect of the contracting muscle is located distal of the small venules, or that in
the microcirculation heterogeneity (see below) is large
and that the decreased arterial inflow and increased venous outflow are only seen in the large vessels as a
summated effect (79).
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layer-dependent differences in the expression patterns of
titin isoforms at least implying differences in diastolic
function of muscles in these layers. The muscle shortening and thickening model and the vascular deformation
model can explain differences in the layers, because
shortening of the cardiac muscle fibers, and thus vascular
deformation, are most prominent in the subendocardium.
The three models also predict deformation of the transmural vessels in systole, which results in a decrease in
perfusion pressure of the subendocardial layers (Fig. 19).
A quantitative comparison between the effect of intramyocardial pressure and the effect of an increased
pressure gradient over the transmural vessels on subendocardial flow is not available.
Model calculations show (Fig. 21) that when the
varying elastance, intramyocardial pressure, and muscle
shortening are taken into account, their contributions
depend on the myocardial layer (426). It may also be seen
from these calculations that for isovolumic contractions
where muscle shortening is small, pressure and muscle
stiffness play the major role, whereas for isobaric contractions, shortening is an important contributor to flow
impediment. This is a strong argument favoring a role for
both mechanisms (via ventricular pressure and direct
effects) depending on the layers and condition of contraction.
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µ
Physiol Rev • VOL
behave the same way. Diameter or volume changes of
coronary resistance vessels in control and vasodilation
can be measured in the intact heart using high-speed NMR
(165), and this could potentially open the way to study the
microvasculature during the cardiac cycle in the in vivo
heart.
That complete collapse of vessels is not taking place
argues against an intramyocardial pressure in the subendocardium that is close to ventricular pressure. This is
especially the case for thin-walled venules where a much
larger pressure outside than inside the vessel would result
in complete collapse. The waterfall model and intramyocardial pump model predict that with an intramyocardial
pressure close to ventricular lumen pressure, both arteriole and venule would be compressed in systole. That a
complete vascular collapse does not occur is an argument
in favor of the varying elastance model, the muscle shortening and thickening model, and the vascular deformation
model (see also sect. IIID6). This can be understood as
follows: local effects of contraction produce a local interstitial pressure, but the magnitude of this pressure depends also on how easily interstitial fluid can move out
and how blood from the vessels can be pumped out. If the
local volume is constant (“isovolumic”), the intramyocardial pressure will be high. When blood is pumped out,
interstitial pressure will be much lower. Veins are a lowpressure system and thin walled, and the displacement of
the blood can be large so that intramyocardial pressure in
the vicinity of the veins is small and they will not be
compressed more than the arterioles. Calculations by Vis
et al. (427) show that indeed diameter changes in arte-
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µ
The waterfall model and the intramyocardial pump
model are made to explain the global effects of contraction on arterial inflow (and venous outflow) only. The
varying elastance model, the muscle shortening and thickening model, and the vascular deformation model predict,
depending on the local behavior of the cardiac muscle,
what happens (250). However, their applicability to the
microcirculation has not been tested.
B) DIAMETERS IN THE MICROCIRCULATION. Neither subendocardial arterioles nor subendocardial venules are completely
compressed (collapsed) in systole (305, 422, 452, 166). In
fact, both the diameter of the small subendocardial artery
and vein change in the order of 11 and 30%, respectively,
around their mean during the cardiac cycle (Fig. 22, B–D).
Hiramatsu et al. (166) reported similar results on diameter
changes in venules and arterioles. The diameter changes
in arteriole and venule (Fig. 22B) while blood is pumped
out against a high pressure in the arteriole, and a low
pressure in the venule is roughly similar in pattern as well.
This suggests that intravascular pressure does not increase much in the venule, thereby protecting the venular
diameter from large changes. The diameter of the subepicardial arteriole changes little during contraction, while
the diameter of the subendocardial arteriole decreases by
⬃30% (Fig. 22, C and D). It has been reported that capillary volume and thus capillary diameter vary little between diastole and systole in arrested, i.e., static, conditions (405). Whether or not this is also the case in the
beating heart remains unclear. Nevertheless, because subendocardial diameters of arterioles and venules both vary
over the cardiac cycle in a similar manner (Fig. 22B)
(440), it is reasonable to assume that the capillaries also
FIG. 22. A: red blood cell velocity in
subepicardial arterioles (12.8 ⫾ 4.1 ␮m),
capillaries and venules (16.5 ⫾ 6.5 ␮m). The
arteriolar velocity graph is repeated for
comparison. [Adapted from Ashikawa et al.
(21).] B: the diameter changes in a subendocardial arteriole and venule. Both the venule
and arteriole do not collapse under the external pressure. [Adapted from Yada et al.
(452).] C and D: diameter changes and flow
velocity in subepicardial (left) and subendocardial (right) arterioles. The R signifies the
R-wave in the ECG. [Adapted from Toyota
et al. (406).]
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
Physiol Rev • VOL
principle, able to account for heterogeneity of perfusion,
but needs to be developed in further detail.
D) VENULES PROTECT ARTERIOLES FROM COLLAPSE. If an arteriole
is accompanied by, or is in close proximity to, venules,
the venules will decrease in size during contraction,
thereby “unloading” the interstitium, giving a lower intramyocardial pressure, and protecting the arteriole. It
has been calculated that the thin-walled vein with lower
intraluminal pressure varies ⬃30% in diameter and the
change in arteriolar diameter is only ⬃10% (Fig. 23). Thus
the resistance arteries are protected from changes by the
variations in venular diameter (428). This theoretical prediction is partly supported by experimental data. Subendocardial arterioles and venules both decrease by ⬃10%
in diameter is systole (166), which is roughly in line with
the prediction of Vis et al. (426). Yada and co-workers
(451, 452) reported that the change in subendocardial
diameters depends on vasomotor tone, which changes the
vascular mechanical properties. Hiramatsu et al. (166)
showed that in systole, an intramyocardial arteriole, when
accompanied by a venule, decreased in diameter, while
the venular diameter was not affected. So apparently,
direct coupling between arterioles and venules is not
sufficiently described by the model of Vis et al. (426). Note
that the accompaniment of arterioles and venules is species dependent (217–219).
In summary, At the microcirculatory level, flows are
not clearly showing arteriolar systolic flow impediment
and venular flow augmentation, while these phenomena
are obvious in flows measured in large epicardial arteries
FIG. 23. When an arteriole is accompanied by two venules, the
effect of cardiac contraction is mainly on the venules. The venules, with
low pressure and thin wall, are easily emptied and change in diameter
while the arteriole is “protected.” [Adapted from Vis et al. (428).]
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rioles and venules are not considerably different, and
measurements show the same (Figs. 17 and 21).
The roughly similar effects of contraction on venular
and arteriolar diameters could suggest that capillary diameter changes will also be of the same magnitude. Because the arterial compartment (arteries ⬎200 ␮m), the
venous compartment (veins ⬎200 ␮m), and the capillary
compartment all account for ⬃30 – 40% of the coronary
blood volume (218), all compartments contribute similarly to the volume changes and the intramyocardial
pump.
C) HETEROGENEITY OF FLOW. In the maximally dilated heart
in diastole, where the role of both smooth muscle and
cardiac muscle contraction is minimal, it can be assumed
that perfusion heterogeneity is determined by the vascular anatomy. Models based on fractal branching patterns
can give an explanation based on the anatomy (33, 213–
215). However, metabolic flow regulation (158) and local
effects of contraction are expected to play a role, and
local perfusion is then not determined by the vascular
anatomy alone. Nevertheless, fractal flow patterns have
been reported in the regulating coronary bed as well (29,
30, 32, 33, 96).
The waterfall model (111) and intramyocardial pump
model (376, 378) account for layer differences, i.e., more
coronary flow impediment in subendocardial layers than
in subepicardial layers in systole (111, 137). The varying
elastance model (245–249) was originally presented as a
lumped model as well. The calculations by Vis et al. (426)
can, in principle, account for heterogeneity of coronary
flow if there is heterogeneity in muscle behavior. However, this has not been worked out quantitatively, and no
experimental data are available. Intramyocardial pressure
depends on the local “load” of the interstitium as mentioned above (see also sect. IIID6). This means that with
heterogeneity in muscle contraction and in vessel density
and size, heterogeneity in impediment can arise. Similarly,
local differences in muscle shortening and thus thickening may cause flow heterogeneity. Deformation of the
vasculature may also depend on the region. In addition to
these effects, it appears that isolated subendocardial and
subepicardial arteries respond somewhat differently to
transvascular pressure pulsations (374).
Comprehensive models are needed to account for
heterogeneity, shape changes, and different effects of
contraction on layers in the wall (128) and their interaction. Most models are based on the effect of contraction
via ventricular pressure only and cannot explain heterogeneity. Models now being developed should include local
effects (41, 42, 66, 369 –371, 427– 429) and thus give new
insight into local coronary flows, diameters, and intramyocardial pressure (369).
The waterfall model and intramyocardial pump
model only explain the global effect of contraction on
coronary perfusion. The other group of models is, in
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6. Intramyocardial pressure
A) MEASUREMENT OF INTRAMYOCARDIAL PRESSURE. Many attempts to measure intramyocardial pressure, starting with
those of Gregg (152) and more recently by others (40, 162,
162, 297, 327), were carried out to relate intramyocardial
pressure and flow impediment (124, 175, 309, 376, 443).
The methods are summarized in Figure 24 and discussed
in the legend. The closed method mimics contractions
where the interstitial cavity is under “isovolumic” conditions (see below), and the perfusion method mimics what
happens to blood flow during contraction, including vascular emptying. The three other methods measure pressure in, presumably, the interstitium, and it is not clear
whether the local “cavity” is in an “isovolumic” condition
(see below). The micropipette method probably causes
the smallest amount of damage, but whether this small
cavity can be considered isovolumic is not known and
difficult to determine.
B) INTRAMYOCARDIAL PRESSURE EXPLAINED. The varying elastance model pertains not only to the ventricular lumen,
but to the interstitium as well (Figs. 16 and 24). Furthermore, the pressure in the interstitium depends on the
varying stiffness of the cardiac muscle and on the “load”
on the cavity where pressure is measured. If the cavity
behaves “isovolumic” (compare the isovolumically contracting ventricle), measured pressure will be high. If the
FIG. 24. Methods to measure intramyocardial
pressure. The open method simply introduces a
small, fluid-filled catheter in the muscle, and pressure is measured with an external transducer. In
the closed method, a small tube with a closed end
is introduced into the ventricular wall. In this way
an “isovolumic” intramyocardial pressure is measured. In the perfusion method, a thin tube is
threaded through the wall; the tube is perfused
with a constant pressure, and the flow impediment is measured. In the solid state method, a
catheter-tip manometer, usually with recessed
sensor tip, is inserted in the wall and pressure is
measured. With the micropipette method, a very
small micropipette (⬃7 ␮m) is inserted in the
wall, and pressure is obtained using the servo-null
technique; with this method damage is presumably minimal.
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and veins. The waterfall model and intramyocardial pump
model are global models, accounting for differences in the
effects of cardiac contraction in different layers, but not
for heterogeneity. The varying elastance model, the muscle shortening and thickening model, and the vascular
deformation model can explain local differences when
heterogeneity in cardiac muscle contraction exists. Further studies are required to quantify the effects of heterogeneity of cardiac muscle contraction on local flow.
The changes in diameters of both arterioles and
venules are not much different, and venules do not collapse in systole. This is difficult to explain with the high
intramyocardial pressure predicted by the waterfall
model and intramyocardial pump model. The varying elastance model, the muscle shortening and thickening
model, and the vascular deformation model suggest another explanation for intramyocardial pressure (see sect.
IIID6) and can explain that diameter changes in arterioles
and venules are of the same order.
The thin-walled low-pressure venules can protect arterioles in their proximity from strong diameter decreases
in systole because the venules “unload” the interstitium,
resulting in a lower intramyocardial pressure. Models
need to be developed to match the local, heterogeneous
effects of cardiac muscle contraction with the global effects of cardiac contraction on coronary flow.
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
In summary, analogous to what happens in the ventricular cavity, the measured intramyocardial pressure
depends not only on cardiac muscle contraction, but also
on how the cavity, where it is measured, behaves. If the
cavity is behaving “isovolumically,” i.e., no volume displacement, intramyocardial pressure is high. If the vessels
(venules and arterioles) and the, local, interstitial space
can be emptied, i.e., when the volume can be pumped out
(“low load”), the intramyocardial pressure development
due to contraction will be small. Thus intramyocardial
pressure depends on mechanical cross-talk and is not
simply related to ventricular pressure as assumed by the
waterfall model and intramyocardial pump model.
7. Flow reserve and supply-to-demand ratio
CFR (see above) is the ratio of flows during maximal
vasodilation and reference conditions. It depends on the
resistance of the stenosis and that of the microcirculation.
Cardiac contraction affects the coronary microvasculature in systole, and the magnitude of this effect depends
on the cardiac contraction and the mechanical properties
of the vasculature, which in turn depends on the vasoactive state. Thus the CFR depends not only on the severity
of the stenosis but also on the effect of cardiac contraction on microcirculatory resistance. The effect of contrac-
FIG. 25. The varying elastance hypothesis applied to the interstitium. A: the interstitial or intramyocardial pressure is considered as a “lumen”
with surrounding cardiac muscle. The muscle properties change, causing an increase in elastance of the cavity in systole. Intramyocardial pressure
depends on the elastance increase and the ease with which fluid can leave the interstitial space or with which blood and lymph vessels can empty.
B: intramyocardial pressures are shown in diastole and systole in control (isovolumic, “working”) and isobaric (“nonworking”) beats. The increase
in intramyocardial pressure in systole is still present in isobaric contractions, supporting the varying elastance hypothesis. [Adapted from Mihailescu
and Abel (297).]
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sensor causes damage and interstitial fluid leaks out
(compare ejecting ventricle), the measured variations in
pressure over the cardiac cycle will be low. This may
explain the variation in the reports on intramyocardial
pressure (443).
The measurements of intramyocardial pressure using
the servo-null method, thereby causing minimal damage
(163, 164, 297), show that intramyocardial pressure increases from the subepicardium to the subendocardium.
However, the dependence on ventricular pressure is limited. Even for isobaric beats where ventricular pressure is
negligible, intramyocardial pressure is still considerable
(Fig. 25). Kresh et al. (251) showed that intramyocardial
pressure in the subendocardium may be higher than ventricular pressure. These findings can be considered evidence that intramyocardial pressure is not directly proportional to and always smaller than ventricular lumen
pressure. Both the waterfall model and the intramyocardial pump model assume that for isobaric beats, when no
ventricular pressure is generated, intramyocardial pressure is negligible as well, and thus flow impediment is not
expected. Nevertheless, flow impediment under these
conditions is found (see Fig. 15). During both isovolumic
and isobaric contractions, the varying elastance, muscle
shortening and thickening, and vascular deformation
models have an effect on the interstitium, blood vessels,
and flow.
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E. Cardiac Contraction Augments Coronary Flow
It has been shown in the intact heart (332), and in
isolated coronary vessels (126, 143, 323, 373, 374), that
cyclic vascular or transmural (143) pressures affect
smooth muscle tone. This effect may be direct (143) or
through endothelial mediators, such as endothelium-derived hyperpolarization factor (126, 323) or nitric oxide
(NO) (373, 374). Altman et al. (10) were one of the first to
show that NO syntheses inhibition during exercise antagonized coronary vasodilation. Also longitudinal (axial)
cyclic stretch affects the cytoskeleton of (renal artery)
endothelium, together with vascular reactivity (363). It
can therefore be hypothesized that cardiac contraction,
through external pressure and deformation of the vascular wall, including the endothelial cells, can also affect
smooth muscle tone. Compression of the entire heart,
large enough for coronary flow to stop, as surrogate for
externally induced changes in vessel diameter due to
contraction, is followed by reactive hyperemia as a result
of vasodilation. The hyperemic response is qualitatively
similar to the well-known short coronary artery occlusion
(341), which is also followed, after release, by a reactive
hyperemia (Fig. 26). Both the compression- and occlusion-induced hyperemia are eliminated by inhibition of
NO synthesis using NG-nitro-L-arginine methyl ester (LPhysiol Rev • VOL
FIG. 26. Top: reactive hyperemia obtained by external cardiac
compression, mimicking extravascular compression (Ext Pr), and coronary artery occlusion in control (top 2 tracings) and after L-NAME
(bottom 2 tracings). The top tracing shows mean coronary flow as a
function of time following a coronary occlusion and as a result of
external cardiac compression, as indicated by the second tracing. In
both interventions, flow is stopped and hyperemia follows. However, the
hyperemia following coronary occlusion is smaller than the one caused
by compression. Bottom: after NO blockade by L-NAME, the hyperemia
has disappeared (bottom 2 tracings). It is therefore concluded that
compression of the coronary vasculature by application of an external
pressure, and most likely also by cardiac muscle contraction, is affecting
vasomotor tone through NO signaling. [Adapted from Sun et al. (388).]
NAME) (388). Gattulo et al. (133) also showed that NO is
involved in reactive hyperemia. Apparently the diameter
changes of the vessels, resulting from pulse pressure
(332) or from cardiac contraction and compression, have
an effect on the endothelium and vasoreactivity.
This indirect dilatory effect of cardiac muscle contraction on the coronary vasculature may in part compensate for the direct compression of the vasculature and the
flow impediment.
In summary, cardiac contraction, through changes in
transmural pressure, results in release of mediators contributing to vasodilation. It is suggested that longitudinal
stretch of the vessels also has an effect.
F. Effects of Cardiac Muscle on the Coronary
Vasculature: Summary
Mechanical cross-talk depends on the mechanical
properties of the cardiac muscle (contractility) and the
mechanical properties of the vasculature (vasomotor
tone).
In diastole, the effect of the cardiac muscle on the
coronary arteries and arterioles is controversial, but probably small. The diastolic cardiac muscle does determine
venous compliance. The effects of cardiac filling and papillary muscle length on coronary flow depend on the
working muscle length and the amount of stretch, which
may, in part, explain the differences.
In systole the cardiac muscle has an effect on arteries, arterioles, and veins, and contraction impedes arterial
inflow and augments coronary venous outflow. The main
effects take place in the smaller intramyocardial vessels.
These global findings are not clearly mirrored in the mi-
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tion may be avoided by determining pressure-flow relationships in diastole only (280).
The FFR is the ratio of the maximal flow in the bed
perfused by the stenosed artery and the maximal flow in
a normal, unstenosed area. When muscle contractility
differs between these areas, for instance, when cardiac
muscle contractility is higher in the normal region than in
the region distal of the stenosis, maximal flow in the
reference region is underestimated and the FFR is not a
good measure of the stenosis severity.
The supply-to-demand ratio assumes that the effect
of cardiac contraction (on the subendocardial layers) is
such that coronary perfusion is negligible in systole. The
systolic flow impediment in systole depends on cardiac
contractility and ventricular pressure. Therefore, flow in
subendocardial layers may not always be negligible in
systole, thereby making the supply-to-demand ratio meaningless.
In summary, the CFR and the FFR depend on the
effect of cardiac muscle contraction on the coronary vasculature. Thus these parameters may not give the correct
information about the severity of a stenosis. The supplyto-demand ratio assumes negligible systolic flow in subendocardial layer. However, subendocardial systolic flow
depends on cardiac muscle contraction and, when this
flow is not negligible, the supply-to-demand ratio is meaningless.
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
have shown that when regional contraction is abolished
and elastance is small, ventricular pressure has an effect
on the vasculature or starts to play a more prominent role
(108, 243, 317). Pagliaro et al. (317) have shown that for
low left ventricular pressures, the major determinant of
flow impediment is contractility, while at high left ventricular pressure, the pressure is most important (317). It
was also shown that lymph vessels are protected from
collapse from high ventricular pressure by the stiff systolic muscle (160, 418). Epicardial lymph pressure during
stop flow was shown to depend on ventricular pressure
(161).
However, experimental quantification is still limited
because intramyocardial pressure is difficult to measure
and depends on local “load” (443). Moreover, muscle
shortening and thickening and vessel deformation at the
micro scale are also difficult to quantify. The overall
picture of factors contributing to coronary flow impediment is qualitatively summarized in Figure 27.
Detailed models of global pressure-flow relationships
exist (41, 42, 66, 369 –371, 427– 429) but are, in general,
only based on the intramyocardial pressure being proportional to ventricular pressure. Thus the effect of contraction on layers is included and the predictions can be
tested against experiments (128, 264). However, comprehensive models including the contribution of (local) muscle contraction are necessary to incorporate the local
effects. In this way, heterogeneity, local effects of con-
FIG. 27. Comprehensive summary of the effect of cardiac contraction on the coronary vasculature. Cardiac muscle contraction causes, apart
from the heart acting as a pump and generating ventricular pressure, a pumping action on the interstitium and vasculature. The two major
mechanisms of cardiac muscle contraction on the coronary vasculature are as follows: the contraction of the cardiac muscle cells generates a
ventricular pressure, which in turn generates an intramyocardial pressure. Increased intramyocardial pressure causes a decrease in transmural
pressure and vascular diameters. The waterfall model and the intramyocardial pump model are based on this effect. The cardiac muscle cells
contract and thereby stiffen, shorten, and thicken. Increased cardiac muscle stiffness decreases vascular diameters and volume, giving a pumping
action. In addition, interstitial volumes decrease, thereby producing an intramyocardial pressure. Muscle shortening and thickening in ejecting
contractions lead to vascular deformation (changes in branching angles, tortuosity) and vascular volume changes. The varying elastance model, the
muscle shortening and thickening model, and the vascular deformation model are based on these effects. Both of these major effects play a role.
Their contribution depends on the type of contraction and on the layer in the heart wall (subendocardium or subepicardium). In isobaric ventricular
contractions and in the isolated papillary muscle, the first mechanism does not contribute.
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crocirculation. Two basic mechanisms play a role in coronary flow impediment in systole.
First, the muscle-generated tension produces a pressure in the ventricular lumen, and through this pressure
an intramyocardial pressure is generated, in such a way
that it decreases from subendocardium to subepicardium.
In other words the ventricular pressure is a necessary
intermediate step in the flow impediment. The waterfall
model and intramyocardial pump model are based on this
mechanism.
Second, muscle contraction per se results in increased stiffness of the muscle and in shortening, and
thickening, thereby deforming the vasculature. The varying elastance model, the muscle shortening and thickening model, and vascular deformation model are based on
this mechanism and explain a direct effect on the vasculature. Muscle contraction also results in an intramyocardial pressure that depends on the local “load” (443). Data
on isolated papillary muscle show flow impediment (9),
which can only be explained on the basis of the direct
effect of muscle contraction on the vasculature and not
through ventricular pressure because there is no lumen
present. The summary is given in Figure 27.
Calculations by Vis and co-workers (426 – 429) (Fig.
21) show that both mechanisms contribute to flow impediment depending on the way the heart contracts (isovolumically or isobarically) and on the layer in the heart wall
(subendocardial or subepicardial). Several publications
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traction, shape changes of the vasculature (324, 325), and
the interaction of these effects can be accounted for and
perhaps translated into the global effects of contraction.
IV. THE CORONARY VASCULATURE AFFECTS
THE CARDIAC MUSCLE
A. Coronary Flow and Cardiac Muscle in Diastole
In 1960, Salisbury et al. (343) demonstrated that alterations in coronary perfusion changed diastolic left ventricular distensibility. This phenomenon was attributed to
an “erectile effect” of the coronary vasculature. Although
some investigators could not reproduce this effect (1,
398), it is generally agreed that an increase in coronary
perfusion shifts the diastolic ventricular pressure-volume
relationship upward and leftward, leading to increased
ventricular stiffness (89, 121, 130, 131, 287, 289, 304, 313,
334, 431, 449). However, there is discussion whether flow
is related to shear force or to pressure in the vasculature,
or both (212).
Interpretation of the mechanism of how perfusion
affects diastolic stiffness is complicated in the whole
heart due to the complex geometry of heart and vasculature (31, 383), metabolic limitations (431), and lack of
accurate measurement of wall stress (177). In isolated
perfused papillary muscle, where vessels and muscle fibers predominantly run in parallel and metabolic demand
is not limited by perfusion (354), coronary arterial pressure shifts the diastolic stress-strain relationship upward
and to the left (Fig. 28) (8). In addition, a crossover point
is seen at low stress, and below this crossover point the
effect of coronary perfusion on the stress-strain relationship is reversed. When stress-strain relationships of isolated blood vessels in the longitudinal, i.e., axial direction,
are studied for different distending or perfusion pressures, a crossover point is also found (441, 442). A twocomponent model, as shown in Figure 29, consisting of
vessels and muscle cells in parallel, shows that the effect
of perfusion (in terms of coronary vascular filling) on the
cardiac muscle can be explained by changes in mechanical behavior of the vasculature in the axial direction
rather than by formation of edema or changes in cardiac
muscle properties (8). Thus the diastolic pressure-volume
relationship of the heart is not only determined by the
muscle characteristics and extracellular matrix, but also,
Physiol Rev • VOL
FIG. 28. Coronary perfusion has a mechanical effect on the diastolic
force-length relationship of cardiac muscle. Increased perfusion pressure makes the blood vessels stiffer in their axial direction. Therefore, in
the isolated papillary muscle, where vessels and muscle fibers predominantly are parallel, the whole muscle becomes stiffer as well. At very
small stretch (strain), close to slack length, a crossover point is found.
The crossover point results from vascular properties. [Adapted from
Allaart et al. (8).]
to a small extent, by coronary perfusion pressure through
changes in mechanical cross-talk between vasculature
and cardiac muscle.
For the intact ventricle, this implies that at low ventricular filling pressures an increase in coronary perfusion
pressure augments ventricular filling, whereas at high
ventricular filling pressures the vasculature contributes to
protection against overstretching of the ventricle. The
crossover point is in the low physiological range, since it
occurs at ⬃10% above slack length of the cardiac muscle.
In the physiological range of muscle lengths and ventricular volumes, an increased perfusion pressure increases
the diastolic pressure-volume relationship of the ventricle
towards a stiffer behavior (8, 287, 289, 304, 313, 431).
In summary, the diastolic pressure-volume relationship of the ventricle is affected by vascular filling through
changes in vessel mechanics. In the physiological range of
muscle lengths, the increased vascular filling increases
diastolic stiffness, but the effect is small.
B. Coronary Flow and Cardiac Muscle in Systole
In this section we discuss the effect of coronary
filling and perfusion on the cardiac muscle. Vascular filling or perfusion exerts an effect on the contracting cardiac muscle by two mechanisms.
An increase in the microvascular volume opens
stretch-activated channels, and Ca2⫹ influx in the cardiac
muscle cells is increased followed by an increase in calcium sensitivity of the contractile apparatus (Gregg effect).
Vascular emptying augments cardiac muscle contraction by a direct effect.
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In this section we discuss the influences of the coronary vasculature and its perfusion on the diastolic properties of the heart and on cardiac contraction. The effects
of coronary perfusion on cardiac muscle contraction and
oxygen consumption, independent of oxygen supply limitations, are discussed, excluding alleviation of limited
oxygen supply by increasing perfusion.
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
1289
FIG. 29. Model of diastolic cross-talk
between vessels and muscle. The forcelength relationship of isolated blood vessels depends on vascular, transmural pressure and “rotates” around a crossover
point with increasing transmural pressure
(left panel). In the intact perfused cardiac
muscle, the force-length relationship depends on the vessel and muscle properties
combined, and the diastolic relationship
also rotates around a crossover point
(right panel).
In 1958, Gregg and co-workers (157, 291) described
that an increase in coronary perfusion alters cardiac muscle contraction and oxygen consumption, independent of
changes in myocardial oxygen supply, the “Gregg effect.”
Reperfusion is here not considered as part of the Gregg
effect (118). The effect itself and the mechanism on which
it is based have been the subject of discussion over the
last decades, and it has become evident that the Gregg
effect depends on the degree of autoregulation (27, 94, 95,
212). Increased perfusion within the autoregulation range
does not show an increase in (regional) mechanical function or oxygen consumption, implying that with good
autoregulation the Gregg effect is minimal (212, 299, 355,
356, 385). Several experimental studies have suggested
that in stunned myocardium the Gregg phenomenon does
not only apply to oxygen consumption but also to contractile function (382). In the right ventricle, where autoregulation is poor under physiological conditions, the
Gregg effect is consistently found (27, 109). Because autoregulation resides mainly in the microvasculature, it is
likely that the mechanism behind the Gregg effect is
related to alterations in microvascular volume (16, 17, 27,
104, 261, 262, 304, 350, 351, 353).
It was shown that the effect of perfusion on contraction depends more on the contractile state of the muscle
than on the length of the muscle (Fig. 30) (9). From Figure
30 it can be seen that at low contractility (low Ca2⫹
concentration in the external medium) a strong increase
in force takes place with perfusion, while at high contractility (high Ca2⫹ concentration) the increase in force with
perfusion is small. These findings suggest that intracellular Ca2⫹ plays a role in this phenomenon (229). Figure 30
also shows that at similar muscle length force increases
with perfusion, and the changes in the diastolic lengthtension relationship are small with respect to the changes
Physiol Rev • VOL
in the systolic relationships (compare Figs. 28 and 30).
These data indicate that a “garden hose effect,” i.e., a
change in muscle length with an increase in perfusion
pressure (16, 130, 322), plays a minor role. This has been
confirmed by many experimental studies (8, 27, 43, 104,
183, 229, 262, 353) and was well reviewed by Downey et
al. (109). Also, shear stress-induced release of inotropic
endothelial factors has been suggested (101, 103, 432), but
this was not confirmed by experimental findings (261, 262,
329, 330). Finally, the magnitude of the Gregg effect appears to be dependent on the type of metabolic substrate
used (316), with a more pronounced effect in the presence of free fatty acids.
In the context of the above it can be hypothesized
that the Gregg effect is based on microvascular volume
changes that affect the cardiac muscle cell, including its
FIG. 30. The effect of coronary perfusion on cardiac contraction in
the isolated perfused papillary muscle of the rat. For low contractile
state, the perfusion strongly augments cardiac force development. For a
high contractile state, the effect of perfusion is much smaller, but still
present. [Adapted from Schouten et al. (353).]
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1. The Gregg effect
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WESTERHOF ET AL.
33). Both the force and the Ca2⫹ alterations are inhibited
by blockade of stretch-activated ion channels (SACs) with
gadolinium or streptomycin, as indicated by the dashed
lines of Figure 33 (261, 262). The sustained increase in
force, which is still present after the [Ca2⫹]i has returned
to its preintervention level, is also completely inhibited by
blockade of the SACs. It therefore results from changes in
Ca2⫹ sensitivity (261, 262) or endothelin-1 signaling (321),
which are triggered by the initial increase in the intracellular Ca2⫹ transient. The role of NO (Fig. 34) (34, 262),
angiotensin type 1 receptor (321), cytochrome P-450 and
cyclooxygenase (34), the endothelial glycocalyx (340),
FIG. 32. The Gregg effect is based on
alterations in microvascular volume that
affect the cardiac muscle cell, including its
membranous elements. The data are from
the isolated perfused papillary muscle of
the rat. Left: relationship between developed force, coronary flow, and muscle diameter following a sudden, sustained, increase in perfusion, a perfusion step.
Right: the effect of a perfusion impulse.
After a perfusion step, the developed force
(Fdev) increases gradually, starts to decline
after ⬃60 s, and reaches an increased
steady state after ⬃125 s. The muscle diameter increases instantly due to vascular
filling, followed by a gradual increase due
to interstitial filling (muscle length at 100%
maximal force: 4.1 mm; cross-sectional
area: 0.35 mm2). After a perfusion pulse,
the Fdev is transiently increased for ⬃50 s,
whereas muscle diameter returns to basal
values within ⬃10 s. [Adapted from Lamberts et al. (262).]
µ
µ
membrane (Fig. 31). In the isolated, perfused and not
autoregulating papillary muscle, a step increase in coronary perfusion gives a rapid filling of the vasculature,
which results in an initial increase in diameter of the
whole muscle. This increase is followed by a slower increase in muscle diameter due to edema formation (Fig.
32, left). The increase in vascular filling immediately augments force, and this is followed by a slower increase in
force, which subsequently reduces somewhat to reach a
constant, but sustained elevated level. A short pulse of
coronary perfusion, producing a transient volume change,
results in a transient increase in force, lasting ⬃50 s with
negligible edema formation (Fig. 32, right). For both sustained (229, 261, 262) and transient (262) perfusion
changes, the peak intracellular Ca2⫹ transient is altered
concomitantly (as shown for the sustained change in Fig.
FIG. 33. A stepwise increase in coronary perfusion pressure increases developed muscle force (top) and induces a change in the
intracellular Ca2⫹ transient (bottom). Force increases to a new steadystate level, but the Ca2⫹ transient is only temporarily increased. After a
blockade of the stretch-activated channels (using gadolinium, Gd3⫹), a
perfusion increase fails to alter force and Ca2⫹ transient. [Adapted from
Lamberts et al. (261).]
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FIG. 31. Coronary (micro)vascular filling deforms the adjacent muscle, called transverse deformation.
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
and edema formation itself (211) appears to be minimal in
the inotropic response. Apparently, it is the initial change
in muscle diameter, due to vascular volume change (Fig.
31) (27, 262), that triggers the short-term (through increased Ca2⫹ entry) as well as the long-term (through
increased Ca2⫹ sensitivity) increase in force. Because the
Gregg effect is dependent on capillary perfusion (102,
104) and not on the coronary arterial endothelium
through released inotropic substances (101, 103, 329,
330), or affected by changes in venous pressure (67, 232,
303, 433), the location of the SACs is either on the capillary endothelium or on the cardiomyocytes or both.
A point of discussion has been whether the Gregg
effect is related to alterations in coronary pressure or
coronary flow. Although several studies have suggested
that it is alteration in coronary flow (1, 140, 212, 391), it
appears most likely that coronary pressure-induced
changes in microvascular volume determine the Gregg
effect (27, 109, 262). This conclusion is supported by
others (16, 17, 90, 157).
Under normal physiological conditions, the Gregg
effect is small or not observed because autoregulation
prevents the microvascular volume from changing (27, 94,
95, 212). The effect is uncovered during ineffective autoregulation (109), as in the right ventricle or in pathological
situations, such as the onset of hibernation or distal of a
stenosis. In low coronary perfusion, or when autoregulation is ineffective, the Gregg effect may constitute an
immediate mechanism that increases pump function of
Physiol Rev • VOL
the heart following increased coronary perfusion, while
preventing a mismatch between cardiac contractility and
oxygen delivery. In this explanation, the increased oxygen
consumption with increased perfusion is secondary to the
increase in pressure or force, because oxygen consumption is coupled to force development (337, 345, 448).
A) SYSTOLIC STIFFNESS. Another suggested explanation of
the Gregg effect is based on the concept of systolic ventricular stiffness, defined as the slope of the wall forcesegment length relationship in systole (43, 109, 183, 272)
[for details, see Fig. 1 of the publication by Bian and
Downey (43)]. Increased coronary perfusion increases
internal resistance to muscle shortening, which increases
systolic ventricular stiffness. The stiffer left ventricular
wall causes an increase in oxygen demand, since more
energy must be expended to deform the stiffer ventricular
wall during ejection. However, so-defined systolic ventricular stiffness is not a true indicator of cardiac muscle
stiffness alone, but also depends on the afterload, i.e.,
aortic pressure, which in turn is determined by properties
of the systemic vasculature. Thus an increase in systolic
stiffness is not an accurate measure to describe changes
in the cardiac muscle.
In summary, the increase in cardiac muscle contractility with increased coronary perfusion is only found
when autoregulation is weak or absent, suggesting that
the effects are to be found in the microcirculation. Increased vessel filling (“hoop stress”) results in the opening of SACs, giving an increase in intracellular calcium
followed by an increase in calcium sensitivity of the contractile apparatus of the cardiac muscle. The reported
increase in oxygen consumption with increased perfusion
is secondary to the increased contractility.
2. Coronary vascular emptying augments cardiac
contraction
The cardiac muscle diameter increases when the
muscle shortens, because intracellular volume remains
constant. The diameter increase is at the expense of the
coronary vascular diameters and thus on vascular volume
(Fig. 35) (144), which results in a decrease in arterial
inflow (flow impediment) and an increase in venous outflow in systole, as discussed above.
The alterations in vascular volume have been viewed
as merely a consequence of the compressive forces generated by the contraction of the surrounding myocardium.
However, because the coronary vasculature is intertwined with the myocardium, emptying of the vasculature
could facilitate cardiomyocyte thickening and hence
shortening. For instance, when the coronary perfusion
medium in perfused rat papillary muscles is made more
viscous (by about a factor of 10, with Tyrode viscosity is
⬃1 cP, with dextran 500 kDa ⬃10 cP) and the ease of
vascular emptying is decreased, contraction is impeded
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FIG. 34. After a stepwise increase in perfusion, developed muscle
force increases. Blockade of the stretch-activated channels by gadolinium (Gd3⫹) abolishes the increase. NOS inhibition by L-NNA and use of
an NO donor (sodium nitroprusside, SNP) do not affect the response.
[Adapted from Lamberts et al. (262).]
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WESTERHOF ET AL.
FIG. 35. During muscle contraction and
shortening, the muscle cells increase in diameter. The increase in diameter results from an
increase in intracellular pressure. The increased intracellular pressure counteracts the
force generated by the contractile apparatus.
The increase in muscle diameter takes place at
the expense of the coronary vasculature. The
ease of vascular deformation, and thus vascular emptying, determines the intracellular
pressure. Purely fiber-isometric contractions
do not affect the coronary vasculature, and
force generation is not counteracted.
FIG. 36. When the perfusion medium is made more viscous and
vascular emptying is decreased, contraction is impeded. In muscle isometric contractions, force development is decreased (top). This effect is
stronger in the muscle when it shortens (bottom). Vascular emptying
allows muscle thickening during shortening, but when the vasculature
cannot empty, the muscle thickening is impeded and an intracellular
pressure builds up counteracting the tension generated by the contractile apparatus. The dextran results compare to “low Tyrode” perfusion in
terms of flow (Q) and “high Tyrode” perfusion in terms of pressure (P).
[Top panel adapted from Willemsen et al. (450).]
Physiol Rev • VOL
cannot empty, the shortening muscle cannot thicken and
builds up an intracellular pressure. This, in turn, counteracts the tension generated by the contractile apparatus
resulting in a reduction of the net force.
An increase in perfusion pressure increases force
development on the one hand, but impedes vascular emptying to the arterial side, leading to a smaller force on the
other hand. However, most vascular emptying during contraction is by means of venous outflow, because coronary
sinus pressure is low and venular resistance is small. Thus
the net result of these two counteracting effects depends
on the conditions. When autoregulation is strong, and the
Gregg effect is small, increased arterial pressure with
(some) reduction in vascular emptying may lower force.
When autoregulation is poor and the Gregg effect is
strong, vascular emptying to the arterial side is expected
to have little effect.
It has been reported that the addition of dextran
(with a molecular mass of 500 kDa) to the perfusion fluid
in isolated perfused guinea pig hearts decreases contractility by ⬃50% (138). Dextran binds to the endothelial
luminal surface, and this binding affects the shear-sensing
system. For this particular dextran, this effect makes the
force decrease due to decreased vascular emptying even
larger. However, the 50% decrease can only be explained
in part by shear sensing because an endothelium-derived
effect on contractility is at maximum 15% (55, 270) or less
(262). In polycythemia, blood viscosity is increased, but
the increase is from ⬃3 cP at a hematocrit of 40% to ⬃4.5
cP at a hematocrit of 60% (448). Therefore, the effects of
polycythemia on muscle contraction through vascular
emptying are relatively small.
In conclusion, when the intramyocardial pump cannot displace intravascular fluid, muscle contraction is
reduced, but the effect of changes in blood viscosity is
small.
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and force development is decreased (Fig. 36) (340, 450).
No effect is expected in single muscle fibers, or in isolated
muscle preparations and ventricular wall sections, where
all muscle cells would contract isometrically and where
the fibers do not shorten and thus do not thicken. However, during muscle isometric contractions, some of the
fibers shorten and thicken at the expense of the vessels.
In shortening contractions, all muscle fibers shorten and
the effect is larger (Fig. 36, bottom). When muscle fiber
thickening is almost completely prevented by filling the
vasculature with gelatin, or by placing an external stiff
tube around the isolated papillary muscle, the decrease in
force is very pronounced (450).
Thus vascular emptying allows muscle fiber thickening during shortening. However, when the vasculature
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
C. Effects of Coronary Vasculature on Cardiac
Muscle: Summary
We have discussed mechanical cross-talk of the coronary vessels on the cardiac muscle. Coronary perfusion
affects the diastolic ventricular properties through
changes in the lengthwise stiffness of the coronary vasculature. In the face of a limitation of oxygen supply, an
increase in perfusion enhances cardiac muscle contractility via the increased oxygen supply. However, the Gregg
phenomenon pertains to the effect of an increased perfusion on myocardial contractility and subsequently on oxygen consumption independent of changes in myocardial
oxygen supply. The Gregg effect is only seen when autoregulation is poor so that microvascular volume can
change with perfusion. The first step in the mechanism is
opening of stretch-sensitive channels, and thereby increasing intracellular [Ca2⫹]i, followed by an increase in
Ca2⫹ sensitivity.
Physiol Rev • VOL
Coronary vascular emptying plays a role in cardiac
muscle contraction. When vascular emptying is impeded,
cardiac muscle cell thickening is diminished, intracellular
pressure builds up, and development of the force generated by the contractile apparatus of the cell is counteracted so that net force is reduced. This mechanism is
always in action even during autoregulation.
V. ROLE OF THE EXTRACELLULAR MATRIX
IN CROSS-TALK
Although myocardial pump function is based on contraction of the myocytes, the predominant cell type in the
heart is the fibroblast. The major role of the fibroblasts is
deposition of the extracellular matrix (ECM). The ECM of
the heart consists of an integrated collagen, fibrin, and
elastin network, which maintains tissue integrity and intercellular communication (62, 63, 187, 188, 244, 438). The
cardiac extracellular collagen matrix comprises 2– 6% of
left ventricular dry weight (439). Over the last decades,
several studies reported interventions with the collagen
structure, using many different techniques, to study the
effects of extracellular matrix on contraction in healthy
and diseased hearts (28, 44, 64, 68, 221, 250, 263, 276, 284,
311, 384, 396, 403, 460). Excessive collagen deposition or
pathological fibrosis has been associated with left ventricular dysfunction, hypertension, myocardial ischemia, and
heart failure. Three major changes have been described:
1) a change in collagen content, 2) a conformational
change in collagen type (type III decreases, type I increases), and 3) an increase in collagen cross-linking.
Most of these studies confirm the notion (62, 276, 437)
that the extracellular collagen matrix prevents overstretching of sarcomeres during filling by increasing passive stiffness at higher pressures and serve to maintain
the unloaded geometry in the ventricle. Although there
are prominent consequences for cardiac function when
the collagen matrix structure is altered, knowledge regarding the role of the matrix in mechanical cross-talk is
limited.
A. Theoretical Suggestions
Although one might assume that an accumulation of
ECM proteins increases tissue stiffness and adversely
affects myocardial muscle shortening and viscoelasticity,
it is unknown whether increased collagen content, e.g.,
during hypertrophy and heart failure, particularly affects
coronary flow properties and impediment during cardiac
contraction. Several analyses and suggestions have been
given about the role of the extracellular matrix in crosstalk. Beyar et al. (40) presented the effect of the interconnecting collagen fibers in a model simulation. Gosse and
Clementy (139) suggested that during cardiac hypertro-
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How changes in venous outflow affect cardiac contraction has not been well established. In the blood-perfused dog heart, elevated coronary sinus pressure was
shown to increase ventricular wall volume and decrease
diastolic ventricular compliance (434). Increased venous
outflow pressure was also shown to increase the intramyocardial pressure, thereby increasing the zero-flow
pressure intercept of pressure-flow relationships (185). It
was also shown that increased coronary sinus pressure
has either a negative effect on contraction (67, 178, 434)
or little or no effect (232, 303, 433, 457). These differences
may, in part, be explained by the role of a waterfall
mechanism (339), arising from smooth muscle tone
and/or from cardiac muscle contraction, since changes in
venous pressure below the waterfall pressure are not
expected to have an effect on coronary flow and vascular
emptying. It was also shown that the effect of increasing
coronary sinus pressure was different in systole and diastole (301, 302, 346), suggesting that not only the smooth
muscle tone-related waterfall plays a role, but also the
waterfall resulting from cardiac contraction. Increases in
coronary venous pressure should always be referenced
against the magnitude of the waterfall, and it can only
then be studied how coronary flow responds.
In summary, muscle contraction, with shortening,
results in a build-up of intracellular pressure, which produces muscle thickening. Vascular emptying allows the
cardiac muscles to thicken more easily so that intracellular pressure is lower. This lower intracellular pressure
counteracts the tension developed by the contractile apparatus to a lesser extent. The result is an increase in
muscle tension in systole. Increased arterial pressure has
a small or negligible effect on emptying, but an increase in
venous pressure can have a negative effect on cardiac
contraction by decreasing vascular emptying.
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B. Experimental Findings
Recently some experimental data have been published. Lamberts et al. (263) investigated the effects of
removal of the collagen struts, connecting vasculature
and cardiac muscle, using collagenase in the isolated
perfused papillary muscle of the rat. They found that
removal did not affect coronary flow in diastole and did
not alter systolic flow impediment (Fig. 37). Moreover, the
systolic change in muscle diameter was not altered, showing that emptying of the coronary vasculature during contraction was also not affected. In spontaneously hyper-
tensive rats, the collagen content was reduced using collagenase and an advanced glycation end-product (AGE)
cross-link breaker, without any effects on coronary blood
flow, coronary flow reserve (see above), or coronary resistance (392). These data indicate that the collagen struts
are not important in directly and acutely ameliorating
coronary flow impediment as suggested from long-term
clinical observations (15, 396, 399, 460).
Charan et al. (67) showed in sheep hearts that edema
induced by augmented coronary venous pressure did not
influence total coronary flow. Lamberts et al. (263) observed edema formation after collagenase treatment but
did not observe changes in diastolic flow and flow impediment with the edema. These findings suggest that the
direct effect of the matrix on the vasculature and the
indirect effects resulting from edema play a minor role,
and may counteract each other.
Thus, contrary to expectations and theoretical models, the role of the extracellular matrix on systolic flow
impediment appears to be small. Perhaps this role is of
importance in extreme conditions, such as an enlarged
ventricle. Experimental evidence is still too scant to provide a clear image of the role of the extracellular matrix in
cross-talk.
C. Summary
On the basis of the limited information available, it
appears that the extracellular matrix exerts its effect
mainly on cardiac contraction via diastolic and systolic
properties of the heart rather than on cross-talk with the
coronary circulation.
VI. CONCLUSIONS
FIG. 37. The effect of collagen type I removal on diastolic flow and
systolic flow impediment in isolated perfused papillary muscle of the rat
at a length of 95% Lmax during isometric contractions is not significant.
[Adapted from Lamberts et al. (263).]
Physiol Rev • VOL
This physiological review reports on the mechanical
cross-talk between the cardiac muscle and the coronary
vasculature in the normal heart and normal isolated myocardium. The major aspects of cross-talk are summarized
in Figure 38.
A major part of the mechanical cross-talk in the
normal heart takes place at the level of the microcirculation. Although many studies have been concerned with
the diseases of the larger, epicardial, coronary arteries, it
has recently become clear that the intramyocardial coronary vasculature, which is in close contact with the cardiac muscle, is often affected and of great importance for
muscle perfusion. Especially in coronary heart disease,
but also in hypertrophy and failure, where the muscle
cells of the vasculature and their distances are changed,
mechanical cross-talk may be different.
Coronary arterial inflow and local perfusion can be
measured noninvasively, and information on the conduit
arteries and the coronary intramyocardial vasculature has
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phy, the increased thickness and stiffness of the ventricular wall might additionally stress the coronary vasculature due to an increase in systolic and, especially, diastolic pressure.
The extracellular collagen structure between cardiac
muscle cells and the coronary vasculature, in particular
the collagen struts, have been proposed to decrease the
effect of cardiac contraction on the vasculature by preventing collapse of the capillaries in systole (2, 46), and to
increase interstitial pressure in diastole (312). It was also
proposed that the collagen fibers affect the transmission
of radial forces, which in turn play a role in the generation
of intramyocardial pressure (40). Additionally, it has been
suggested that myocardial edema, probably as a result of
structural alterations of the collagen matrix, decreases
vascular lumens and may affect coronary flow as well
(462). However, these suggestions have not been confirmed experimentally, either because the critical experiments were not performed or the experiments did not
support these suggestions.
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
been obtained in the patient (see sect. I and Ref. 336). MRI
allows for noninvasive measurement of local myocardial
strains. However, local fiber stress or tension cannot be
measured and can only be derived through model calculations (18, 177). The presently available basic knowledge
on cardiac mechanics, coronary morphology, finite element modeling, and computational flow dynamics, together with new measurement techniques, should make it
possible to better understand the cross-talk on a more
detailed scale and open the way to studying and quantifying its role in the microcirculation.
A. Cardiac Muscle Affects the
Coronary Vasculature
The data in the literature regarding the effect of the
diastolic cardiac muscle on the coronary vasculature are
not consistent, and probably depend on the reference
conditions chosen. The effects in diastole depend on the
(changes in) muscle length and appear, in the physiological range of ventricular volumes, to be small. More experiments under well-defined conditions and reconsideration of the models are necessary.
Coronary flow is affected by cardiac muscle contraction through two interacting, and simultaneously acting,
mechanisms. The models based on these mechanisms are
summarized in Figure 27. The first mechanism invokes the
intermediary effect of ventricular pressure that generates
intramyocardial pressure acting on the vasculature (waterfall model and intramyocardial pump model) and the
second mechanism is through a direct effect on the vasculature (varying elastance model, muscle shortening and
thickening model, and vascular deformation model). The
magnitudes of their contributions depend on the mechanical properties of the cardiac muscle (e.g., contractility)
and the mechanical properties of the vasculature (e.g.,
Physiol Rev • VOL
vasomotor tone). The effects therefore depend on the
layer in the heart wall (subepicardial or subendocardial)
and on the way the heart contracts (isovolumic, isobaric).
In the arrested heart in systole, the flow is smaller
than when arrested in diastole, and the coronary resistance and intercept pressure are increased. The waterfall
model explains this through an increased intercept pressure, while the other models predict an increase in resistance, either by a diameter decrease or by vascular deformation. During rhythmic contractions, the vascular volume changes cause the resistance change, while the rate
of change of the vascular volume results in “pumping.”
This pump action results in arterial inflow impediment
and venous outflow augmentation. Except for the waterfall model, all the models explain these effects.
The two mechanisms differ with respect to the prediction of what happens with an increase in contractility.
The direct mechanisms predict an increased flow impediment when cardiac contractility increases. The mechanisms acting through ventricular pressure require that
ventricular pressure be increased with increased contractility. However, since the load on the heart determines
ventricular pressure as well, increased contractility does
not always parallel an increased ventricular pressure (Fig.
15), and thus intramyocardial pressure. Although some
quantitative analysis has been performed (see Fig. 21),
and some modeling of these effects has been carried out
(459), the solid experimental quantitative analysis of the
two mechanisms and their relative contributions to coronary flow impediment is still lacking. Many detailed models account only for the effect of contraction through
ventricular pressure (450, 452, 455). However, models
accounting for the direct effects of muscle contraction are
still limited (53, 66, 292).
Coronary flow reserve depends on the microcirculation, and thus on the effect of cardiac muscle contraction.
The fractional flow reserve assumes that the bed distal of
the stenosis and the normal bed are similarly influenced
by cardiac muscle contraction. With possible differences
in cardiac muscle contractility, maximal flow in these
beds may differ, and errors in fractional flow reserve may
occur.
The supply of oxygen mainly depends on diastolic
flow, and thus on the diastolic time fraction. However,
even a small flow in systole, especially at high heart rates,
can contribute to perfusion and is affected by cardiac
contraction, making the supply-to-demand ratio dependent on mechanical cross-talk.
In the maximally dilated heart in diastole, where the
role of both smooth muscle and cardiac muscle contraction is minimal, it can be assumed that perfusion heterogeneity is determined by the vascular anatomy. Especially
those models based on fractal branching patterns can give
an explanation based on the anatomy (33, 213). However,
local perfusion is not only determined by the vascular
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FIG. 38. Summary of the major mechanisms of mechanical
cross-talk.
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Physiol Rev • VOL
In cardiac hypertrophy, the coronary vasculature
changes, but it is not entirely clear how. In cardiac hypertrophy obtained through hypertension, a significant decrease in both myocardial arteriolar and capillary density
has been reported (52, 268). However, in hypertrophy due
to volume overload, the microcirculation was reported to
grow proportionally (69), and in renal hypertension capillary density in heart muscle is decreased (11). In hypertrophy where minimal microvascular resistance is increased, flow reserve is decreased (220), but this does not
directly affect cardiac function at rest (146). The lower
pressure limit of autoregulation is shifted to higher pressures, which suggests that lowering blood pressure is not
beneficial, but vasodilation is (146, 328, 397).
The pulsations in coronary arterial inflow depend on
the wave shape of the perfusion pressure (aortic pressure) and on the pattern and effect of cardiac muscle
contraction and the variations in coronary arterial input
impedance. Tadaoka and co-workers (393, 394) have
shown that in patients with hypertrophy caused by hypertension, but with normal arteriograms, diastolic coronary
arterial inflow is impaired. Gibson et al. (135) showed that
after myocardial infarction the amplitude of the pulsations in flow, even after correction for the changes in
pressure, appears to increase.
B. Coronary Vasculature Affects the
Cardiac Muscle
In this review we only reported on the effects of the
coronary vasculature on the cardiac muscle independent
of changes in myocardial oxygen supply.
The diastolic pressure-volume relationship of the
ventricle is affected by vascular filling through changes in
vessel mechanics, but the effect is small.
Cardiac contraction is augmented by the coronary
vasculature through two mechanisms. First, increased
vascular filling (“hoop stress”) results in the opening of
SACs, giving an increase in intracellular calcium followed
by an increase in calcium sensitivity of the contractile
apparatus of the cardiac muscle. The reported increase in
oxygen consumption with increased perfusion is secondary to the increased contractility. The increased cardiac
muscle contractility with increased coronary perfusion, in
the absence of oxygen limitation, is only found when
autoregulation is weak or absent, suggesting that the
effects are to be found in the microcirculation.
Second, muscle contraction, with shortening, results
in a build-up of intracellular pressure, which gives muscle
thickening. Vascular emptying allows the cardiac muscles
to thicken more easily so that intracellular pressure is
lower. This lower intracellular pressure counteracts the
tension developed by the contractile apparatus to a lesser
extent. The result is an increase in muscle tension in
systole.
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anatomy, but local autoregulation (158) and local effects
of contraction are important as well.
At the microcirculatory level, flow and red blood cell
velocity do not clearly show arteriolar systolic flow impediment and venular flow augmentation (Fig. 22), while
these phenomena are obvious in epicardial arteries and
veins. These findings emphasize the importance of the
direct and local effects of cardiac muscle contraction on
flow. Changes in diameter of intramyocardial venules and
arterioles are of the same order, and venules do not
collapse in systole (Fig. 22). The waterfall model and
intramyocardial pump model assume that intramyocardial pressure is proportional to ventricular pressure and
thus predict that this pressure is higher than venular
pressure in most layers of the wall, and higher than arteriolar pressure in subendocardial layers. Thus these vessels are predicted to collapse in systole, which is not in
line with the experimental findings (Fig. 22).
The varying elastance model, the muscle shortening
and thickening model, and the vascular deformation
model exert their effects locally depending on muscle
contraction and the local “load.” Analogous to what happens in the ventricular cavity, the measured intramyocardial pressure depends not only on cardiac muscle contraction, but also on how the vessels (venules and arterioles) and the local interstitial space can be emptied.
Therefore, heterogeneity in intramyocardial pressure exists, and intramyocardial pressure development close to
the coronary veins and venules is small so that they will
not collapse. Similarly, the thin-walled low-pressure
venules can protect arterioles in their proximity from
strong diameter decreases in systole (Fig. 23).
Models describing perfusion heterogeneity have been
proposed (53, 66, 292, 426 – 429). However, the contributions of local contraction effects and metabolism as part
of an explanation for perfusion heterogeneity need to be
worked out both experimentally and theoretically. Quantification of the effects is difficult, but is important because infarcts are often of a heterogeneous and of a
“patchy” character (47).
The coronary microcirculation can be affected exclusively (syndrome X, anginal chest pain, positive exercise
test, and angiographically normal coronary arteries) so
that even with normal epicardial arteries angina may
arise. The angina may be due to the increased microcirculatory resistance and through an increase in the effect
of the intramyocardial pump so that flow reversal in systole increases (180). The coronary flow reserve and fractional flow reserve are dependent on the changes that
occur in the (normal) intramyocardial vasculature (223)
and are decreased with increased resistance. It has been
reported that in hypertensive patients without epicardial
lesions, coronary flow reserve is decreased before muscle
mass is increased (14, 54), showing the importance of the
coronary vasculature.
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
4.
5.
6.
7.
8.
9.
10.
11.
C. Extracellular Matrix
12.
The extracellular matrix plays an important role in
the diastolic pressure-volume relationship of the ventricle
(276), as well as in the generation of muscle tension and
ventricular pressure (62). However, the few data that
exist suggest that the direct effect of the extracellular
matrix in mechanical cross-talk is small. It is therefore
suggested that the changes of the extracellular matrix in
hypertrophy and aging do not cause alterations in crosstalk. Nevertheless, experimental protocols should be developed to test this.
It is concluded that on the one hand cardiac contraction impedes coronary flow, but on the other hand vascular emptying augments cardiac contraction.
13.
14.
15.
16.
17.
18.
ACKNOWLEDGMENTS
Address for reprint requests and other correspondence: N.
Westerhof, Lab for Physiology, VU University Medical Center,
Van der Boechorststraat 7, 1081-BT Amsterdam, The Netherlands (e-mail: [email protected]).
20.
GRANTS
21.
This study was supported by Netherlands Heart Foundation Grants 89 – 084, 92–372, 94 – 069, and 96 – 024 and by Netherlands Organization for Scientific Research Grant 902–16-175.
REFERENCES
19.
22.
23.
1. Abel RM and Reis RL. Effects of coronary blood flow and perfusion pressure on left ventricular contractility in dogs. Circ Res 27:
961–971, 1970.
2. Abovsky M, Lanir Y, and Nevo E. Tethering affects the mechanics of coronary capillaries. J Biomech 29: 597– 607, 1996.
3. Akasaka T, Yoshikawa J, Yoshida K, Hozumi T, Takagi T, and
Okura H. Comparison of relation of systolic flow of the right
Physiol Rev • VOL
24.
25.
coronary artery to pulmonary artery pressure in patients with and
without pulmonary hypertension. Am J Cardiol 78: 240 –244, 1996.
Akasaka T, Yoshikawa J, Yoshida K, Maeda K, Takagi T, and
Miyake S. Phasic coronary flow characteristics in patients with
hypertrophic cardiomyopathy: a study by coronary Doppler catheter. J Am Soc Echocardiogr 7: 9 –19, 1994.
Aldea GS, Mori H, Husseini WK, Austin RE, and Hoffman JI.
Effects of increased pressure inside or outside ventricles on total
and regional myocardial blood flow. Am J Physiol Heart Circ
Physiol 279: H2927–H2938, 2000.
Alders DJ, Groeneveld AB, de Kanter FJ, and van Beek JH.
Myocardial O2 consumption in porcine left ventricle is heterogeneously distributed in parallel to heterogeneous O2 delivery. Am J
Physiol Heart Circ Physiol 287: H1353–H1361, 2004.
Alegria JR, Herrmann J, Holmes DR Jr, Lerman A and Rihal
CS. Myocardial bridging. Eur Heart J 26: 1159 –1168, 2005.
Allaart CP, Sipkema P, and Westerhof N. Effect of perfusion
pressure on diastolic stress-strain relations of isolated rat papillary
muscle. Am J Physiol Heart Circ Physiol 268: H945–H954, 1995.
Allaart CP and Westerhof N. Effect of length and contraction on
coronary perfusion in isolated perfused papillary muscle of rat
heart. Am J Physiol Heart Circ Physiol 271: H447–H454, 1996.
Altman JD, Kinn J, Duncker DJ, and Bache RJ. Effect of
inhibition of nitric oxide formation on coronary blood flow during
exercise in the dog. Cardiovasc Res 28: 119 –124, 1994.
Amann K, Neimeier KA, Schwarz U, Tornig J, Matthias S,
Orth SR, Mall G, and Ritz E. Rats with moderate renal failure
show capillary deficit in heart but not skeletal muscle. Am J
Kidney Dis 30: 382–388, 1997.
Anrep GV, Cruickshank EW, Downing AC, and Subba Rau A.
The coronary circulation in relation to the cardiac cycle. Heart 14:
111–133, 1927.
Anrep GV and Saalfeld EV. The effect of the cardiac contraction
upon the coronary flow. J Physiol 79: 317–331, 1933.
Antony I, Nitenberg A, Foult JM, and Aptecar E. Coronary
vasodilator reserve in untreated and treated hypertensive patients
with and without left ventricular hypertrophy. J Am Coll Cardiol
22: 514 –520, 1993.
Anversa P, Olivetti G, Melissari M, and Loud AV. Morphometric study of myocardial hypertrophy induced by abdominal aortic
stenosis. Lab Invest 40: 341–349, 1979.
Arnold G, Kosche F, Miessner E, Neitzert A, and Lochner W.
The importance of the perfusion pressure in the coronary arteries
for the contractility and the oxygen consumption of the heart.
Pflügers Arch 299: 339 –356, 1968.
Arnold G, Morgenstern C, and Lochner W. The autoregulation
of the heart work by the coronary perfusion pressure. Pflügers
Arch 321: 34 –55, 1970.
Arts T, Bovendeerd PH, Prinzen FW, and Reneman RS. Relation between left ventricular cavity pressure and volume and systolic fiber stress and strain in the wall. Biophys J 59: 93–102, 1991.
Arts T and Reneman RS. Analysis of intramyocardial pressure
(IMP). A model study. Bibl Anat 103–107, 1977.
Arts T and Reneman RS. Interaction between intramyocardial
pressure (IMP) and myocardial circulation. J Biomech Eng 107:
51–56, 1985.
Ashikawa K, Kanatsuka H, Suzuki T, and Takishima T. Phasic
blood flow velocity pattern in epimyocardial microvessels in the
beating canine left ventricle. Circ Res 59: 704 –711, 1986.
Austin RE Jr, Aldea GS, Coggins DL, Flynn AE and Hoffman
JI. Profound spatial heterogeneity of coronary reserve. Discordance between patterns of resting and maximal myocardial blood
flow. Circ Res 67: 319 –331, 1990.
Austin RE Jr, Smedira NG, Squiers TM, and Hoffman JI.
Influence of cardiac contraction and coronary vasomotor tone on
regional myocardial blood flow. Am J Physiol Heart Circ Physiol
266: H2542–H2553, 1994.
Aversano T, Klocke FJ, Mates RE, and Canty JM Jr. Preloadinduced alterations in capacitance-free diastolic pressure-flow relationship. Am J Physiol Heart Circ Physiol 246: H410 –H417, 1984.
Baan J Jr, Steendijk P, Mikuniya A, and Baan J. Systolic
coronary flow reduction in the canine heart in situ: effects of left
86 • OCTOBER 2006 •
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Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017
The contributions of these two mechanisms to cardiac contraction have only been quantified to a limited
extent (Figs. 30 and 36). Isolated perfused papillary muscle and the isolated cardiac muscle cell without vasculature (413) appear to be preparations where these mechanisms could be compared (8, 9, 262, 450).
It has not been quantitatively investigated whether or
not the changes in the vasculature during hypertrophy
cause differences in the effects of the vessels on muscle
contraction. With relatively fewer vessels and a relatively
smaller intravascular volume in this condition, vascular
emptying is more difficult. Therefore, intracellular pressure is increased in systole, which results in a smaller
force generation. Experiments should be designed to investigate this important issue.
Cardiac contraction affects vascular diameters and
thereby causes coronary inflow impediment, but at the
same time emptying of the vasculature enhances muscle
contraction.
1297
1298
26.
27.
28.
29.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
ventricular pressure and elastance. Basic Res Cardiol 91: 468 – 478,
1996.
Bach RG, Kern MJ, Donohue TJ, Caracciolo EA, Aguirre FV,
and Moore JA. Dynamic systolic coronary flow reversal and hyperemia in left anterior descending coronary blood flow velocity
during Valsalva maneuver in a patient with hypertrophic cardiomyopathy. Cathet Cardiovasc Diagn 34: 67–71, 1995.
Bai XJ, Iwamoto T, Williams AG Jr, Fan WL, and Downey HF.
Coronary pressure-flow autoregulation protects myocardium from
pressure-induced changes in oxygen consumption. Am J Physiol
Heart Circ Physiol 266: H2359 –H2368, 1994.
Baicu CF, Stroud JD, Livesay VA, Hapke E, Holder J, Spinale
FG, and Zile MR. Changes in extracellular collagen matrix alter
myocardial systolic performance. Am J Physiol Heart Circ Physiol
284: H122–H132, 2003.
Bassingthwaighte JB, Beard DA, and Li Z. The mechanical and
metabolic basis of myocardial blood flow heterogeneity. Basic Res
Cardiol 96: 582–594, 2001.
Bassingthwaighte JB, King RB, and Roger SA. Fractal nature of
regional myocardial blood flow heterogeneity. Circ Res 65: 578 –
590, 1989.
Bassingthwaighte JB, Yipintsoi T, and Harvey RB. Microvasculature of the dog left ventricular myocardium. Microvasc Res 7:
229 –249, 1974.
Bauer WR, Hiller KH, Galuppo P, Neubauer S, Kopke J, Haase
A, Waller C, and Ertl G. Fast high-resolution magnetic resonance
imaging demonstrates fractality of myocardial perfusion in microscopic dimensions. Circ Res 88: 340 –346, 2001.
Beard DA and Bassingthwaighte JB. The fractal nature of myocardial blood flow emerges from a whole-organ model of arterial
network. J Vasc Res 37: 282–296, 2000.
Beaucage P, Massicotte J, Jasmin G, and Dumont L. Role of
nitric oxide synthase, cytochrome P-450, and cyclooxygenase in
the inotropic and lusitropic cardiac response to increased coronary
perfusion. J Cardiovasc Pharmacol 40: 96 –105, 2002.
Bedaux WL, Hofman MB, Visser CA, and van Rossum AC.
Simultaneous noninvasive measurement of blood flow in the great
cardiac vein and left anterior descending artery. J Cardiovasc
Magn Reson 3: 227–235, 2001.
Bellamy RF. Diastolic coronary artery pressure-flow relations in
the dog. Circ Res 43: 92–101, 1978.
Bellamy RF and O’Benar JD. Cessation of arterial and venous
flow at a finite driving pressure in porcine coronary circulation.
Am J Physiol Heart Circ Physiol 246: H525–H531, 1984.
Berne RM. Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am J Physiol 204: 317–322, 1963.
Berne RM. Regulation of coronary blood flow. Physiol Rev 44:
1–29, 1964.
Beyar R, Ben Ari R, Gibbons-Kroeker CA, Tyberg JV, and
Sideman S. Effect of interconnecting collagen fibres on left ventricular function and intramyocardial compression. Cardiovasc Res
27: 2254 –2263, 1993.
Beyar R, Caminker R, Manor D, and Sideman S. Coronary flow
patterns in normal and ischemic hearts: transmyocardial and artery
to vein distribution. Ann Biomed Eng 21: 435– 458, 1993.
Beyar R, Manor D, Zinemanas D, and Sideman S. Concepts and
Controversies in Modelling Coronary Circulation. Berlin:
Springer, 1993.
Bian X and Downey HF. Right coronary pressure modulates right
ventricular systolic stiffness and oxygen consumption. Cardiovasc
Res 42: 80 – 86, 1999.
Bing OH, Fanburg BL, Brooks WW, and Matsushita S. The
effect of lathyrogen beta-amino proprionitrile (BAPN) on the mechanical properties of experimentally hypertrophied rat cardiac
muscle. Circ Res 43: 632– 637, 1978.
Bishop AH and Samady H. Fractional flow reserve: critical review
of an important physiologic adjunct to angiography. Am Heart J
147: 792– 802, 2004.
Borg TK and Caulfield JB. The collagen matrix of the heart.
Federation Proc 40: 2037–2041, 1981.
Borggreve M, Breithardt G, and Wolper C. Ventricular tachycardia. In: Cardiology, edited by Crawford MH, Dimarco JP, and
Paulus WJ. St. Louis, MO: Mosby, 2004.
Physiol Rev • VOL
48. Bouma P, Sipkema P, and Westerhof N. Coronary arterial inflow
impediment during systole is little affected by capacitive effects.
Am J Physiol Heart Circ Physiol 264: H715–H721, 1993.
49. Bouma P, Sipkema P, and Westerhof N. Vasomotor tone affects
diastolic coronary flow and flow impediment by cardiac contraction similarly. Am J Physiol Heart Circ Physiol 266: H1944 –H1950,
1994.
50. Braakman R, Sipkema P, and Westerhof N. Steady state and
instantaneous pressure-flow relationships: characterisation of the
canine abdominal periphery. Cardiovasc Res 17: 577–588, 1983.
51. Braakman R, Sipkema P, and Westerhof N. Two zero-flow
pressure intercepts exist in autoregulating isolated skeletal muscle.
Am J Physiol Heart Circ Physiol 258: H1806 –H1814, 1990.
52. Breisch EA, White FC, Nimmo LE, and Bloor CM. Cardiac
vasculature and flow during pressure-overload hypertrophy. Am J
Physiol Heart Circ Physiol 251: H1031–H1037, 1986.
53. Bruinsma P, Arts T, Dankelman J, and Spaan JA. Model of the
coronary circulation based on pressure dependence of coronary
resistance and compliance. Basic Res Cardiol 83: 510 –524, 1988.
54. Brush JE Jr, Cannon RO III, Schenke WH, Bonow RO, Leon
MB, Maron BJ, and Epstein SE. Angina due to coronary microvascular disease in hypertensive patients without left ventricular
hypertrophy. N Engl J Med 319: 1302–1307, 1988.
55. Brutsaert DL. Cardiac endothelial-myocardial signaling: its role in
cardiac growth, contractile performance, and rhythmicity. Physiol
Rev 83: 59 –115, 2003.
56. Brzezinska AK, Merkus D, and Chilian WM. Metabolic communication from cardiac myocytes to vascular endothelial cells. Am J
Physiol Heart Circ Physiol 288: H2232–H2237, 2005.
57. Burattini R, Borgdorff P, Gross DR, Baiocco B, and Westerhof
N. Systemic autoregulation counteracts the carotid baroreflex.
IEEE Trans Biomed Eng 38: 48 –56, 1991.
58. Burattini R, Sipkema P, van Huis GA, and Westerhof N. Identification of canine coronary resistance and intramyocardial compliance on the basis of the waterfall model. Ann Biomed Eng 13:
385– 404, 1985.
59. Canetti M, Akhter MW, Lerman A, Karaalp IS, Zell JA, Singh
H, Mehra A, and Elkayam U. Evaluation of myocardial blood flow
reserve in patients with chronic congestive heart failure due to
idiopathic dilated cardiomyopathy. Am J Cardiol 92: 1246 –1249,
2003.
60. Canty JM Jr, Klocke FJ, and Mates RE. Pressure and tone
dependence of coronary diastolic input impedance and capacitance. Am J Physiol Heart Circ Physiol 248: H700 –H711, 1985.
61. Canty JM Jr, Klocke FJ, and Mates RE. Characterization of
capacitance-free pressure-flow relations during single diastoles in
dogs using an RC model with pressure-dependent parameters. Circ
Res 60: 273–282, 1987.
62. Caulfield JB and Borg TK. The collagen network of the heart.
Lab Invest 40: 364 –372, 1979.
63. Caulfield JB and Janicki JS. Structure and function of myocardial fibrillar collagen. Technol Health Care 5: 95–113, 1997.
64. Caulfield JB and Wolkowicz P. Inducible collagenolytic activity
in isolated perfused rat hearts. Am J Pathol 131: 199 –205, 1988.
65. Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, and
Camici PG. Coronary microvascular dysfunction and prognosis in
hypertrophic cardiomyopathy. N Engl J Med 349: 1027–1035, 2003.
66. Chadwick RS, Tedgui A, Michel JB, Ohayon J, and Levy BI.
Phasic regional myocardial inflow and outflow: comparison of
theory and experiments. Am J Physiol Heart Circ Physiol 258:
H1687–H1698, 1990.
67. Charan NB, Ripley R, and Carvalho P. Effect of increased coronary venous pressure on left ventricular function in sheep. Respir
Physiol 112: 227–235, 1998.
68. Charney RH, Takahashi S, Zhao M, Sonnenblick EH, and Eng
C. Collagen loss in the stunned myocardium. Circulation 85: 1483–
1490, 1992.
69. Chen Y, Torry RJ, Baumbach GL, and Tomanek RJ. Proportional arteriolar growth accompanies cardiac hypertrophy induced
by volume overload. Am J Physiol Heart Circ Physiol 267: H2132–
H2137, 1994.
86 • OCTOBER 2006 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017
30.
WESTERHOF ET AL.
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
Physiol Rev • VOL
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
its perfusion in the anaesthetized goat. J Physiol 419: 703–715,
1989.
Dankelman J, Stassen HG, and Spaan JA. System analysis of
the dynamic response of the coronary circulation to a sudden
change in heart rate. Med Biol Eng Comput 28: 139 –148, 1990.
Dankelman J, Stassen HG, and Spaan JA. Interaction between
Gregg’s phenomenon and coronary flow control: a model study.
Med Biol Eng Comput 37: 742–749, 1999.
Dankelman J, Van der Ploeg CP, and Spaan JA. Transients in
myocardial O2 consumption after abrupt changes in perfusion pressure in goats. Am J Physiol Heart Circ Physiol 270: H492–H499,
1996.
De Bruyne B, Bartunek J, Sys SU, Pijls NH, Heyndrickx GR,
and Wijns W. Simultaneous coronary pressure and flow velocity
measurements in humans. Feasibility, reproducibility, and hemodynamic dependence of coronary flow velocity reserve, hyperemic
flow versus pressure slope index, and fractional flow reserve. Circulation 94: 1842–1849, 1996.
De Bruyne B, Baudhuin T, Melin JA, Pijls NH, Sys SU, Bol A,
Paulus WJ, Heyndrickx GR, and Wijns W. Coronary flow reserve calculated from pressure measurements in humans. Validation with positron emission tomography. Circulation 89: 1013–
1022, 1994.
DeFily DV and Chilian WM. Coronary microcirculation: autoregulation and metabolic control. Basic Res Cardiol 90: 112–118, 1995.
Deussen A, Flesche CW, Lauer T, Sonntag M, and Schrader J.
Spatial heterogeneity of blood flow in the dog heart. II. Temporal
stability in response to adrenergic stimulation. Pflügers Arch 432:
451– 461, 1996.
De Wit C, Roos F, Bolz SS, and Pohl U. Lack of vascular
connexin 40 is associated with hypertension and irregular arteriolar vasomotion. Physiol Genomics 13: 169 –177, 2003.
Dijkman MA, Heslinga JW, Allaart CP, Sipkema P, and
Westerhof N. Reoxygenated effluent of Tyrode-perfused heart
affects papillary muscle contraction independent of cardiac perfusion. Cardiovasc Res 33: 45–53, 1997.
Dijkman MA, Heslinga JW, Sipkema P, and Westerhof N.
Perfusion-induced changes in cardiac O2 consumption and contractility are based on different mechanisms. Am J Physiol Heart Circ
Physiol 271: H984 –H989, 1996.
Dijkman MA, Heslinga JW, Sipkema P, and Westerhof N.
Perfusion-induced changes in cardiac contractility and oxygen consumption are not endothelium-dependent. Cardiovasc Res 33: 593–
600, 1997.
Dijkman MA, Heslinga JW, Sipkema P, and Westerhof N.
Perfusion-induced changes in cardiac contractility depend on capillary perfusion. Am J Physiol Heart Circ Physiol 274: H405–H410,
1998.
Divekar A, Auslender M, Colvin S, Artman M, and Rutkowski
M. Abnormal right coronary artery flow and multiple right ventricular myocardial infarctions associated with severe right ventricular
systolic hypertension. J Am Soc Echocardiogr 14: 70 –72, 2001.
Dole WP, Alexander GM, Campbell AB, Hixson EL, and
Bishop VS. Interpretation and physiological significance of diastolic coronary artery pressure-flow relationships in the canine
coronary bed. Circ Res 55: 215–226, 1984.
Dole WP and Bishop VS. Influence of autoregulation and capacitance on diastolic coronary artery pressure-flow relationships in
the dog. Circ Res 51: 261–270, 1982.
Doucette JW, Goto M, Flynn AE, Austin RE Jr, Husseini WK,
and Hoffman JI. Effects of cardiac contraction and cavity pressure on myocardial blood flow. Am J Physiol Heart Circ Physiol
265: H1342–H1352, 1993.
Downey HF. Coronary-ventricular interaction: the Gregg phenomenon. In: Cardiac-Vascular Remodeling and Functional Interaction, edited by Maryama YH. Berlin: Springer-Verlag, 1997, p. 321–
332.
Downey JM, Downey HF, and Kirk ES. Effects of myocardial
strains on coronary blood flow. Circ Res 34: 286 –292, 1974.
Downey JM and Kirk ES. Inhibition of coronary blood flow by a
vascular waterfall mechanism. Circ Res 36: 753–760, 1975.
Drake-Holland AJ, Laird JD, Noble MI, Spaan JA, and Vergroesen I. Oxygen and coronary vascular resistance during auto-
86 • OCTOBER 2006 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017
70. Chilian WM. Microvascular pressures and resistances in the left
ventricular subepicardium and subendocardium. Circ Res 69: 561–
570, 1991.
71. Chilian WM. Coronary microcirculation in health and disease.
Summary of an NHLBI workshop. Circulation 95: 522–528, 1997.
72. Chilian WM and DeFily DV. Methodological approaches used for
the study of the coronary microcirculation in situ. Blood Vessels 28:
236 –244, 1991.
73. Chilian WM, Eastham CL, Layne SM, and Marcus ML. Small
vessel phenomena in the coronary microcirculation: phasic intramyocardial perfusion and coronary microvascular dynamics.
Prog Cardiovasc Dis 31: 17–38, 1988.
74. Chilian WM, Eastham CL, and Marcus ML. Microvascular distribution of coronary vascular resistance in beating left ventricle.
Am J Physiol Heart Circ Physiol 251: H779 –H788, 1986.
75. Chilian WM and Gutterman DD. Prologue: new insights into the
regulation of the coronary microcirculation. Am J Physiol Heart
Circ Physiol 279: H2585–H2586, 2000.
76. Chilian WM and Layne SM. Coronary microvascular responses to
reductions in perfusion pressure. Evidence for persistent arteriolar
vasomotor tone during coronary hypoperfusion. Circ Res 66: 1227–
1238, 1990.
77. Chilian WM, Layne SM, Eastham CL, and Marcus ML. Heterogeneous microvascular coronary alpha-adrenergic vasoconstriction. Circ Res 64: 376 –388, 1989.
78. Chilian WM, Layne SM, Klausner EC, Eastham CL, and Marcus ML. Redistribution of coronary microvascular resistance produced by dipyridamole. Am J Physiol Heart Circ Physiol 256:
H383–H390, 1989.
79. Chilian WM and Marcus ML. Phasic coronary blood flow velocity
in intramural and epicardial coronary arteries. Circ Res 50: 775–
781, 1982.
80. Chilian WM and Marcus ML. Coronary venous outflow persists
after cessation of coronary arterial inflow. Am J Physiol Heart Circ
Physiol 247: H984 –H990, 1984.
81. Chilian WM and Marcus ML. Effects of coronary and extravascular pressure on intramyocardial and epicardial blood velocity.
Am J Physiol Heart Circ Physiol 248: H170 –H178, 1985.
82. Cinquegrana G, Spinelli L, D’Aniello L, Landi M, D’Aniello
MT, and Meccariello P. Exercise training improves diastolic perfusion time in patients with coronary artery disease. Heart Dis 4:
13–17, 2002.
83. Coffman JD and Gregg DE. Reactive hyperemia characteristics
of the myocardium. Am J Physiol 199: 1143–1149, 1960.
84. Constantinescu AA, Vink H, and Spaan JA. Endothelial cell
glycocalyx modulates immobilization of leukocytes at the endothelial surface. Arterioscler Thromb Vasc Biol 23: 1541–1547, 2003.
85. Cornelissen AJ, Dankelman J, VanBavel E, and Spaan JA.
Balance between myogenic, flow-dependent, and metabolic flow
control in coronary arterial tree: a model study. Am J Physiol
Heart Circ Physiol 282: H2224 –H2237, 2002.
86. Cornelissen AJ, Dankelman J, VanBavel E, Stassen HG, and
Spaan JA. Myogenic reactivity and resistance distribution in the
coronary arterial tree: a model study. Am J Physiol Heart Circ
Physiol 278: H1490 –H1499, 2000.
87. Cornelissen AJ, Spaan JA, Dankelman J, Chan CC, and Yin
FC. Evidence for stretch-induced resistance increase of proximal
coronary microcirculation. Am J Physiol Heart Circ Physiol 281:
H2687–H2696, 2001.
88. Crawford MH, Dimarco JP, Paulus WJ, Asplund K, Aurigemma G, Bakris GL, Crexler H, Falk E, Kato H, and Klein
GJ. Cardiology. St. Louis, MO: Mosby, 2004.
89. Cross CE, Rieben PA, and Salisbury PF. Influence of coronary
perfusion and myocardial edema on pressure-volume diagram of
left ventricle. Am J Physiol 201: 102–108, 1961.
90. Crystal GJ, Downey HF, and Bashour FA. Small vessel and total
coronary blood volume during intracoronary adenosine. Am J
Physiol Heart Circ Physiol 241: H194 –H201, 1981.
91. Dankelman J, Spaan JA, Stassen HG, and Vergroesen I. Dynamics of coronary adjustment to a change in heart rate in the
anaesthetized goat. J Physiol 408: 295–312, 1989.
92. Dankelman J, Spaan JA, Van der Ploeg CP, and Vergroesen I.
Dynamic response of the coronary circulation to a rapid change in
1299
1300
113.
114.
115.
116.
117.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
regulation and metabolic vasodilation in the dog. J Physiol 348:
285–299, 1984.
Duijst P, Westerhof N, and Elzinga G. The lower limit of coronary autoregulation. J Appl Cardiol 3: 353–362, 1988.
Duncker DJ, Ishibashi Y, and Bache RJ. Effect of treadmill
exercise on transmural distribution of blood flow in hypertrophied
left ventricle. Am J Physiol Heart Circ Physiol 275: H1274 –H1282,
1998.
Duncker DJ, van Zon NS, Crampton M, Herrlinger S, Homans
DC, and Bache RJ. Coronary pressure-flow relationship and exercise: contributions of heart rate, contractility, and alpha 1-adrenergic tone. Am J Physiol Heart Circ Physiol 266: H795–H810, 1994.
Duncker DJ, van Zon NS, Pavek TJ, Herrlinger SK, and Bache
RJ. Endogenous adenosine mediates coronary vasodilation during
exercise after K(ATP) channel blockade. J Clin Invest 95: 285–295,
1995.
Duncker DJ, Zhang J, and Bache RJ. Coronary pressure-flow
relation in left ventricular hypertrophy. Importance of changes in
back pressure versus changes in minimum resistance. Circ Res 72:
579 –587, 1993.
Ehring T, Bohm M, and Heusch G. The calcium antagonist
nisoldipine improves the functional recovery of reperfused myocardium only when given before ischemia. J Cardiovasc Pharmacol 20: 63–74, 1992.
Ellis AK and Klocke FJ. Effects of preload on the transmural
distribution of perfusion and pressure-flow relationships in the
canine coronary vascular bed. Circ Res 46: 68 –77, 1980.
Escaned J, Cortes J, Flores A, Goicolea J, Alfonso F, Hernandez R, Fernandez-Ortiz A, Sabate M, Banuelos C, and
Macaya C. Importance of diastolic fractional flow reserve and
dobutamine challenge in physiologic assessment of myocardial
bridging. J Am Coll Cardiol 42: 226 –233, 2003.
Farhi ER, Canty JM Jr, and Klocke FJ. Effects of graded
reductions in coronary perfusion pressure on the diastolic pressure-segment length relation and the rate of isovolumic relaxation
in the resting conscious dog. Circulation 80: 1458 –1468, 1989.
Farhi ER, Klocke FJ, Mates RE, Kumar K, Judd RM, Canty JM
Jr, Satoh S, and Sekovski B. Tone-dependent waterfall behavior
during venous pressure elevation in isolated canine hearts. Circ
Res 68: 392– 401, 1991.
Federici A, Ciccone M, Gattullo D, and Losano G. Systolic and
diastolic changes in human coronary blood flow during Valsalva
manoeuvre. Clin Physiol 20: 19 –29, 2000.
Feigl EO. Coronary physiology. Physiol Rev 63: 1–205, 1983.
Fibich G, Lanir Y, Liron N, and Abovsky M. Modeling of coronary capillary flow. Adv Exp Med Biol 346: 137–150, 1993.
Fisslthaler B, Popp R, Michaelis UR, Kiss L, Fleming I, and
Busse R. Cyclic stretch enhances the expression and activity of
coronary endothelium-derived hyperpolarizing factor synthase.
Hypertension 38: 1427–1432, 2001.
Flynn AE, Coggins DL, Austin RE, Muehrcke DD, Aldea GS,
Goto M, Doucette JW, and Hoffman JI. Nonuniform blood flow
in the canine left ventricle. J Surg Res 49: 379 –384, 1990.
Flynn AE, Coggins DL, Goto M, Aldea GS, Austin RE, Doucette JW, Husseini W, and Hoffman JI. Does systolic subepicardial perfusion come from retrograde subendocardial flow? Am J
Physiol Heart Circ Physiol 262: H1759 –H1769, 1992.
Fokkema DS, VanTeeffelen JW, Dekker S, Vergroesen I, Reitsma JB, and Spaan JA. Diastolic time fraction as a determinant
of subendocardial perfusion. Am J Physiol Heart Circ Physiol 288:
H2450 –H2456, 2005.
Fukui A, Yamaguchi S, Tamada Y, Miyawaki H, Shirakabe M,
Baniya G, and Tomoike H. Increasing coronary perfusion pressure on diastolic and systolic performance is less pronounced in
right ventricle than in left ventricle. Cardiovasc Res 31: 899 –906,
1996.
Gaasch WH and Bernard SA. The effect of acute changes in
coronary blood flow on left ventricular end-diastolic wall thickness. An echocardiographic study. Circulation 56: 593–598, 1977.
Gattullo D, Linden RJ, Losano G, Pagliaro P, and Westerhof
N. Ventricular distension and diastolic coronary blood flow in the
anaesthetized dog. Basic Res Cardiol 88: 340 –349, 1993.
Physiol Rev • VOL
133. Gattullo D, Linden RJ, Losano G, Pagliaro P, and Westerhof
N. Ischaemic preconditioning changes the pattern of coronary
reactive hyperaemia in the goat: role of adenosine and nitric oxide.
Cardiovasc Res 42: 57– 64, 1999.
134. Gattullo D, Losano G, and Vacca G. Integration between myogenic response and neurovegetative activity in the regulation of the
coronary flow. Funct Neurol 5: 193–195, 1990.
135. Gibson CM, Karha J, Murphy SA, de Lemos JA, Morrow DA,
Giugliano RP, Roe MT, Harrington RA, Cannon CP, Antman
EM, Califf RM, and Braunwald E. Association of a pulsatile
blood flow pattern on coronary arteriography and short-term clinical outcomes in acute myocardial infarction. J Am Coll Cardiol 43:
1170 –1176, 2004.
136. Gielen S, Strasser RH, Kubler W, and Haller C. Images in
cardiovascular medicine. Coronary artery ectasia and systolic flow
cessation in hypertrophic cardiomyopathy. Circulation 97: 2372–
2374, 1998.
137. Gold FL and Bache RJ. Transmural right ventricular blood flow
during acute pulmonary artery hypertension in the sedated dog.
Evidence for subendocardial ischemia despite residual vasodilator
reserve. Circ Res 51: 196 –204, 1982.
138. Gonzalez-Castillo C, Rubio R, and Zenteno-Savin T. Coronary
flow-induced inotropism is modulated by binding of dextrans to the
endothelial luminal surface. Am J Physiol Heart Circ Physiol 284:
H1348 –H1357, 2003.
139. Gosse P and Clementy J. Coronary reserve in experimental myocardial hypertrophy. Eur Heart J 16 Suppl I: 22–25, 1995.
140. Goto M, Flynn AE, Doucette JW, Jansen CM, Stork MM,
Coggins DL, Muehrcke DD, Husseini WK, and Hoffman JI.
Cardiac contraction affects deep myocardial vessels predominantly. Am J Physiol Heart Circ Physiol 261: H1417–H1429, 1991.
141. Goto M, Kimura A, Tsujioka K, and Kajiya F. Characteristics of
coronary artery inflow and its significance in coronary pathophysiology. Biorheology 30: 323–331, 1993.
142. Goto M, Tsujioka K, Ogasawara Y, Wada Y, Tadaoka S, Hiramatsu O, Yanaka M, and Kajiya F. Effect of blood filling in
intramyocardial vessels on coronary arterial inflow. Am J Physiol
Heart Circ Physiol 258: H1042–H1048, 1990.
143. Goto M, VanBavel E, Giezeman MJ, and Spaan JA. Vasodilatory effect of pulsatile pressure on coronary resistance vessels.
Circ Res 79: 1039 –1045, 1996.
144. Goto Y, Slinker BK, and Lewinter MM. Effect of coronary
hyperemia on Emax and oxygen consumption in blood-perfused
rabbit hearts. Energetic consequences of Gregg’s phenomenon.
Circ Res 68: 482– 492, 1991.
145. Gould KL. Coronary Artery Stenosis. New York: Elsevier, 1991.
146. Gould KL and Carabello BA. Why angina in aortic stenosis with
normal coronary arteriograms? Circulation 107: 3121–3123, 2003.
147. Gould KL and Lipscomb K. Effects of coronary stenoses on
coronary flow reserve and resistance. Am J Cardiol 34: 48 –55,
1974.
148. Gould KL, Lipscomb K, and Hamilton GW. Physiologic basis for
assessing critical coronary stenosis. Instantaneous flow response
and regional distribution during coronary hyperemia as measures
of coronary flow reserve. Am J Cardiol 33: 87–94, 1974.
149. Grattan MT, Hanley FL, Stevens MB, and Hoffman JI. Transmural coronary flow reserve patterns in dogs. Am J Physiol Heart
Circ Physiol 250: H276 –H283, 1986.
150. Gray H. Gray’s Anatomy. London: Chancellor, 1992.
151. Gregg DE. Coronary Circulation in Health and Disease. Philadelphia, PA: Lea & Febiger, 1950.
152. Gregg DE and Eckstein RW. Measurements of intramyocardial
pressure. Am J Physiol 132: 781–790, 1941.
153. Gregg DE and Green HD. Registration and interpretation of
normal phasic inflow into the left coronary artery by an improved
differential manometric method. Am J Physiol 130: 114 –125, 1940.
154. Gregg DE, Green HD, and Wiggers CJ. Phasic variations in
peripheral coronary resistance and their determinants. Am J
Physiol 112: 362–373, 1935.
155. Gregg DE, Green HD, and Wiggers CJ. The phasic changes in
coronary flow established by differential pressure curves. Am J
Physiol 112: 627– 639, 1935.
86 • OCTOBER 2006 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017
118.
WESTERHOF ET AL.
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
Physiol Rev • VOL
180. Irvine T and Kenny A. Aortic stenosis and angina with normal
coronary arteries: the role of coronary flow abnormalities. Heart
78: 213–214, 1997.
181. Ishibashi Y, Duncker DJ, Zhang J, and Bache RJ. ATP-sensitive
K⫹ channels, adenosine, and nitric oxide-mediated mechanisms
account for coronary vasodilation during exercise. Circ Res 82:
346 –359, 1998.
182. Ishibashi Y, Tanabe K, Oota T, Tanabu K, Sano K, Katou H,
Murakami R, Shimada T, and Morioka S. Phasic right coronary
blood flow in a patient with right ventricular hypertension using
transesophageal Doppler echocardiography. Cardiology 86: 169 –
171, 1995.
183. Iwamoto T, Bai XJ, and Downey HF. Coronary perfusion related
changes in myocardial contractile force and systolic ventricular
stiffness. Cardiovasc Res 28: 1331–1336, 1994.
184. Iwanaga S, Ewing SG, Husseini WK, and Hoffman JI. Changes
in contractility and afterload have only slight effects on subendocardial systolic flow impediment. Am J Physiol Heart Circ Physiol
269: H1202–H1212, 1995.
185. Izrailtyan I, Frasch HF, and Kresh JY. Effects of venous pressure on coronary circulation and intramyocardial fluid mechanics.
Am J Physiol Heart Circ Physiol 267: H1002–H1009, 1994.
186. Jakob M, Spasojevic D, Krogmann ON, Wiher H, Hug R, and
Hess OM. Tortuosity of coronary arteries in chronic pressure and
volume overload. Cathet Cardiovasc Diagn 38: 25–31, 1996.
187. Janicki JS. Myocardial collagen remodeling and left ventricular
diastolic function. Braz J Med Biol Res 25: 975–982, 1992.
188. Janicki JS, Matsubara BB, and Kabour A. Myocardial collagen
and its functional role. Adv Exp Med Biol 346: 291–298, 1993.
189. Janssens S and Lijnen HR. What has been learned about the
cardiovascular effects of matrix metalloproteinases from mouse
models? Cardiovasc Res 69: 585–594, 2006.
190. Johnson PC. Review of previous studies and current theories of
autoregulation. Circ Res 15 Suppl: 9, 1964.
191. Jones CJ, Kuo L, Davis MJ, and Chilian WM. Distribution and
control of coronary microvascular resistance. Adv Exp Med Biol
346: 181–188, 1993.
192. Jones CJ, Kuo L, Davis MJ, and Chilian WM. Myogenic and
flow-dependent control mechanisms in the coronary microcirculation. Basic Res Cardiol 88: 2–10, 1993.
193. Jones CJ, Kuo L, Davis MJ, and Chilian WM. Regulation of
coronary blood flow: coordination of heterogeneous control mechanisms in vascular microdomains. Cardiovasc Res 29: 585–596,
1995.
194. Judd RM and Mates RE. Coronary input impedance is constant
during systole and diastole. Am J Physiol Heart Circ Physiol 260:
H1841–H1851, 1991.
195. Judd RM, Redberg DA, and Mates RE. Diastolic coronary resistance and capacitance are independent of the duration of diastole.
Am J Physiol Heart Circ Physiol 260: H943–H952, 1991.
196. Judd RM, Resar JR, and Yin FC. Rapid measurements of diastolic intramyocardial vascular volume. Am J Physiol Heart Circ
Physiol 265: H1038 –H1047, 1993.
197. Kajiya F. Evaluation of cornary inflow and outflow from myocardium by laser Doppler method. Med Biol Eng Comput 23: 1315–
1316, 1985.
198. Kajiya F, Matsuoka S, Ogasawara Y, Hiramatsu O, Kanazawa
S, Wada Y, Tadaoka S, Tsujioka K, Fujiwara T, and Zamir M.
Velocity profiles and phasic flow patterns in the non-stenotic human left anterior descending coronary artery during cardiac surgery. Cardiovasc Res 27: 845– 850, 1993.
199. Kajiya F, Ogasawara Y, Hiramatsu O, Tachibana H, Goto M,
and Yada T. The relationship between cardiac contraction and
intramyocardial hemodynamics. IEEE Eng Med Biol Mag 16: 127–
132, 1997.
200. Kajiya F, Tomonaga G, Tsujioka K, Ogasawara Y, and Nishihara H. Evaluation of local blood flow velocity in proximal and
distal coronary arteries by laser Doppler method. J Biomech Eng
107: 10 –15, 1985.
201. Kajiya F, Tsujioka K, Goto M, Wada Y, Chen XL, Nakai M,
Tadaoka S, Hiramatsu O, Ogasawara Y, and Mito K. Functional
characteristics of intramyocardial capacitance vessels during diastole in the dog. Circ Res 58: 476 – 485, 1986.
86 • OCTOBER 2006 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017
156. Gregg DE and Sabiston DC Jr. Effect of cardiac contraction on
coronary blood flow. Circulation 15: 14 –20, 1957.
157. Gregg DE. Effect of coronary perfusion pressure or coronary flow
on oxygen usage of the myocardium. Circ Res 13: 497–500, 1963.
158. Groeneveld AB, van Beek JH, and Alders DJ. Assessing heterogeneous distribution of blood flow and metabolism in the heart.
Basic Res Cardiol 96: 575–581, 2001.
159. Hamza LH, Dang Q, Lu X, Mian A, Molloi S, and Kassab GS.
Effect of passive myocardium on the compliance of porcine coronary arteries. Am J Physiol Heart Circ Physiol 285: H653–H660,
2003.
160. Han Y, Vergroesen I, Goto M, Dankelman J, Van der Ploeg CP,
and Spaan JA. Left ventricular pressure transmission to myocardial lymph vessels is different during systole and diastole. Pflügers
Arch 423: 448 – 454, 1993.
161. Han Y, Vergroesen I, and Spaan JA. Stopped-flow epicardial
lymph pressure is affected by left ventricular pressure in anesthetized goats. Am J Physiol Heart Circ Physiol 264: H1624 –H1628,
1993.
162. Heineman FW and Grayson J. Transmural distribution of intramyocardial pressure measured by micropipette technique. Am J
Physiol Heart Circ Physiol 249: H1216 –H1223, 1985.
163. Heslinga JW, Allaart CP, and Westerhof N. Intramyocardial
pressure measurements in the isolated perfused papillary muscle
of rat heart. Eur J Morphol 34: 55– 62, 1996.
164. Heslinga JW, Allaart CP, Yin FC, and Westerhof N. Effects of
contraction, perfusion pressure, and length on intramyocardial
pressure in rat papillary muscle. Am J Physiol Heart Circ Physiol
272: H2320 –H2326, 1997.
165. Hiller KH, Waller C, Voll S, Haase A, Ertl G, and Bauer WR.
Combined high-speed NMR imaging of perfusion and microscopic
coronary conductance vessels in the isolated rat heart. Microvasc
Res 62: 327–334, 2001.
166. Hiramatsu O, Goto M, Yada T, Kimura A, Chiba Y, Tachibana
H, Ogasawara Y, Tsujioka K, and Kajiya F. In vivo observations
of the intramural arterioles and venules in beating canine hearts.
J Physiol 509: 619 – 628, 1998.
167. Hiramatsu O, Goto M, Yada T, Kimura A, Tachibana H, Ogasawara Y, Tsujioka K, and Kajiya F. Diameters of subendocardial arterioles and venules during prolonged diastole in canine left
ventricles. Circ Res 75: 393–397, 1994.
168. Hoffman JI. Why is myocardial ischaemia so commonly subendocardial? Clin Sci 61: 657– 662, 1981.
169. Hoffman JI. Transmural myocardial perfusion. Prog Cardiovasc
Dis 29: 429 – 464, 1987.
170. Hoffman JI. Heterogeneity of myocardial blood flow. Basic Res
Cardiol 90: 103–111, 1995.
171. Hoffman JI. Problems of coronary flow reserve. Ann Biomed Eng
28: 884 – 896, 2000.
172. Hoffman JI. Do we have a gold standard yet? J Am Coll Cardiol
43: 662– 664, 2004.
173. Hoffman JI and Buckberg GD. The myocardial Supply/Demand
ratio: a critical review. Am J Cardiol 41: 327–332, 1978.
174. Hoffman JI and Chilian WM. Brief commentary on coronary
wave-intensity analysis. J Appl Physiol 89: 1633–1635, 2000.
175. Hoffman JI and Spaan JA. Pressure-flow relations in coronary
circulation. Physiol Rev 70: 331–390, 1990.
176. Hofman MB, van Rossum AC, Sprenger M, and Westerhof N.
Assessment of flow in the right human coronary artery by magnetic
resonance phase contrast velocity measurement: effects of cardiac
and respiratory motion. Magn Reson Med 35: 521–531, 1996.
177. Huisman RM, Sipkema P, Westerhof N, and Elzinga G. Comparison of models used to calculate left ventricular wall force. Med
Biol Eng Comput 18: 133–144, 1980.
178. Ilbawi MN, Idriss FS, Muster AJ, DeLeon SY, Berry TE, Duffy
CE, and Paul MH. Effects of elevated coronary sinus pressure on
left ventricular function after the Fontan operation. An experimental and clinical correlation. J Thorac Cardiovasc Surg 92: 231–237,
1986.
179. Ince C, Ashruf JF, Avontuur JA, Wieringa PA, Spaan JA, and
Bruining HA. Heterogeneity of the hypoxic state in rat heart is
determined at capillary level. Am J Physiol Heart Circ Physiol 264:
H294 –H301, 1993.
1301
1302
WESTERHOF ET AL.
Physiol Rev • VOL
222.
223.
224.
225.
226.
227.
228.
229.
230.
231.
232.
233.
234.
235.
236.
237.
238.
239.
240.
gen and ventricular diastolic function. Am J Physiol Heart Circ
Physiol 269: H863–H868, 1995.
Kawamura A, Fujii T, Miura T, Kawabata T, Okamura T,
Yoshitake S, Iida H, Hiro T, Kohno M, and Matsuzaki M.
Abnormal coronary flow profiles at rest and during rapid atrial
pacing in patients with hypertrophic cardiomyopathy. Jpn Circ J
63: 350 –356, 1999.
Kayikcioglu M, Payzin S, Yavuzgil O, Kultursay H, Can LH,
and Soydan I. Benefits of statin treatment in cardiac syndrome-X1.
Eur Heart J 24: 1999 –2005, 2003.
Kenny A, Wisbey CR, and Shapiro LM. Profiles of coronary
blood flow velocity in patients with aortic stenosis and the effect of
valve replacement: a transthoracic echocardiographic study. Br
Heart J 71: 57– 62, 1994.
Kerkhof CJ, Van Der Linden PJ, and Sipkema P. Role of
myocardium and endothelium in coronary vascular smooth muscle
responses to hypoxia. Am J Physiol Heart Circ Physiol 282:
H1296 –H1303, 2002.
Kern MJ, De Bruyne B, and Pijls NH. From research to clinical
practice: current role of intracoronary physiologically based decision making in the cardiac catheterization laboratory. J Am Coll
Cardiol 30: 613– 620, 1997.
Kimura A, Hiramatsu O, Yamamoto T, Ogasawara Y, Yada T,
Goto M, Tsujioka K, and Kajiya F. Effect of coronary stenosis on
phasic pattern of septal artery in dogs. Am J Physiol Heart Circ
Physiol 262: H1690 –H1698, 1992.
King RB and Bassingthwaighte JB. Temporal fluctuations in
regional myocardial flows. Pflügers Arch 413: 336 –342, 1989.
Kitakaze M and Marban E. Cellular mechanism of the modulation of contractile function by coronary perfusion pressure in ferret
hearts. J Physiol 414: 455– 472, 1989.
Kiyooka T, Hiramatsu O, Shigeto F, Nakamoto H, Tachibana
H, Yada T, Ogasawara Y, Kajiya M, Morimoto T, Morizane Y,
Mohri S, Shimizu J, Ohe T, and Kajiya F. Direct observation of
epicardial coronary capillary hemodynamics during reactive hyperemia and during adenosine administration by intravital video microscopy. Am J Physiol Heart Circ Physiol 288: H1437–H1443,
2005.
Klassen GA, Barclay KD, Wong R, Paton B, and Wong AY. Red
cell flux during the cardiac cycle in the rabbit myocardial microcirculation. Cardiovasc Res 34: 504 –514, 1997.
Klautz RJ, Rijk-Zwikker GL, Steendijk P, Wilde J, Teitel DF,
and Baan J. Acute elevation of coronary venous pressure does not
affect left ventricular contractility in the normal and stressed swine
heart: implications for the Fontan operation. J Thorac Cardiovasc
Surg 114: 560 –567, 1997.
Klocke FJ. Coronary blood flow in man. Prog Cardiovasc Dis 19:
117–166, 1976.
Klocke FJ. Measurements of coronary flow reserve: defining
pathophysiology versus making decisions about patient care. Circulation 76: 1183–1189, 1987.
Klocke FJ and Ellis AK. Control of coronary blood flow. Annu
Rev Med 31: 489 –508, 1980.
Klocke FJ, Ellis AK, and Canty JM Jr. Interpretation of changes
in coronary flow that accompany pharmacologic interventions.
Circulation 75: V34 –V38, 1987.
Klocke FJ, Mates RE, Canty JM Jr, and Ellis AK. Coronary
pressure-flow relationships. Controversial issues and probable implications. Circ Res 56: 310 –323, 1985.
Klocke FJ, Weinstein IR, Klocke JF, Romanowski RR, Anbar
RD, Wallmeyer KW, Echt MP, Kraus DR, and Mates RE. Curvilinearity of the diastolic pressure-flow relationship in autoregulating and maximally vasodilated coronary beds; effects on estimates of zero-flow pressure and differences between zero-flow and
intracavitary diastolic pressures. Role of capacitive effects in the
determination of zero-flow pressure from long diastoles. Basic Res
Cardiol 76: 556 –558, 1981.
Klocke FJ and Wittenberg SM. Heterogeneity of coronary blood
flow in human coronary artery disease and experimental myocardial infarction. Am J Cardiol 24: 782–790, 1969.
Koller A and Bagi Z. On the role of mechanosensitive mechanisms eliciting reactive hyperemia. Am J Physiol Heart Circ
Physiol 283: H2250 –H2259, 2002.
86 • OCTOBER 2006 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017
202. Kajiya F, Tsujioka K, Goto M, Wada Y, Tadaoka S, Nakai M,
Hiramatsu O, Ogasawara Y, Mito K, and Hoki N. Evaluation of
phasic blood flow velocity in the great cardiac vein by a laser
Doppler method. Heart Vessels 1: 16 –23, 1985.
203. Kajiya F, Tsujioka K, Ogasawara Y, Hiramatsu O, Wada Y,
Goto M, and Yanaka M. Analysis of the characteristics of the flow
velocity waveforms in left atrial small arteries and veins in the dog.
Circ Res 65: 1172–1181, 1989.
204. Kajiya F, Tsujioka K, Ogasawara Y, Mito K, Hiramatsu O,
Goto M, Wada Y, and Matsuoka S. Mechanical control of coronary artery inflow and vein outflow. Jpn Circ J 53: 431– 439, 1989.
205. Kajiya F, Tsujioka K, Ogasawara Y, Wada Y, Hiramatsu O,
Goto M, Nakai M, Tadaoka S, Matsuoka S, and Sha Y. Effect of
packed cell volume on diastolic coronary artery pressure-flow relations in the dog. Cardiovasc Res 22: 545–554, 1988.
206. Kajiya F, Yada T, Matsumoto T, Goto M, and Ogasawara Y.
Intramyocardial influences on blood flow distributions in the myocardial wall. Ann Biomed Eng 28: 897–902, 2000.
207. Kal JE, Spaan JA, and Van Wezel HB. Calcium channel blockade
with felodipine does not affect metabolic coronary vasodilation in
patients with coronary artery disease. J Cardiovasc Pharmacol 39:
225–233, 2002.
208. Kal JE, Van Wezel HB, Porsius M, Vergroesen I, and Spaan
JA. Metabolic coronary-flow regulation and exogenous nitric oxide
in human coronary artery disease: assessment by intravenous administration of nitroglycerin. J Cardiovasc Pharmacol 35: 7–15,
2000.
209. Kalsho G and Kassab GS. Bifurcation asymmetry of the porcine
coronary vasculature and its implications on coronary flow heterogeneity. Am J Physiol Heart Circ Physiol 287: H2493–H2500,
2004.
210. Kanatsuka H, Ashikawa K, Komaru T, Suzuki T, and Takishima T. Diameter change and pressure-red blood cell velocity
relations in coronary microvessels during long diastoles in the
canine left ventricle. Circ Res 66: 503–510, 1990.
211. Kapelko VI and Khatkevich AN. Dependence of the cardiac
contractile force on the coronary perfusion pressure: difference
between the isovolumic hearts of rat and guinea pig. Cardioscience
6: 25–30, 1995.
212. Karunanithi MK, Young JA, Kalnins W, Kesteven S, and Feneley MP. Response of the intact canine left ventricle to increased
afterload and increased coronary perfusion pressure in the presence of coronary flow autoregulation. Circulation 100: 1562–1568,
1999.
213. Kassab GS. The coronary vasculature and its reconstruction. Ann
Biomed Eng 28: 903–915, 2000.
214. Kassab GS. Functional hierarchy of coronary circulation: direct
evidence of a structure-function relation. Am J Physiol Heart Circ
Physiol 289: H2559 –H2565, 2005.
215. Kassab GS, Berkley J, and Fung YC. Analysis of pig’s coronary
arterial blood flow with detailed anatomical data. Ann Biomed Eng
25: 204 –217, 1997.
216. Kassab GS and Fung YC. Topology and dimensions of pig coronary capillary network. Am J Physiol Heart Circ Physiol 267:
H319 –H325, 1994.
217. Kassab GS, Le KN, and Fung YC. A hemodynamic analysis of
coronary capillary blood flow based on anatomic and distensibility
data. Am J Physiol Heart Circ Physiol 277: H2158 –H2166, 1999.
218. Kassab GS, Lin DH, and Fung YC. Morphometry of pig coronary
venous system. Am J Physiol Heart Circ Physiol 267: H2100 –
H2113, 1994.
219. Kassab GS, Rider CA, Tang NJ, and Fung YC. Morphometry of
pig coronary arterial trees. Am J Physiol Heart Circ Physiol 265:
H350 –H365, 1993.
220. Kataoka T, Hamasaki S, Ishida S, Saihara K, Okui H, Fukudome T, Shinsato T, Mizoguchi E, Ninomiya Y, Otsuji Y, Minagoe S, and Tei C. Contribution of increased minimal coronary
resistance and attenuated vascular adaptive remodeling to myocardial ischemia in patients with systemic hypertension and ventricular hypertrophy. Am J Cardiol 94: 484 – 487, 2004.
221. Kato S, Spinale FG, Tanaka R, Johnson W, Cooper G, and Zile
MR. Inhibition of collagen cross-linking: effects on fibrillar colla-
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
Physiol Rev • VOL
264.
265.
266.
267.
268.
269.
270.
271.
272.
273.
274.
275.
276.
277.
278.
279.
280.
281.
282.
283.
284.
285.
creases diastolic and developed tension in perfused rat papillary
muscle. Am J Physiol Heart Circ Physiol 286: H889 –H894, 2004.
Lamberts RR, Willemsen MJ, Sipkema P, and Westerhof N.
Subendocardial and subepicardial pressure-flow relations in the rat
heart in diastolic and systolic arrest. J Biomech 37: 697–707, 2004.
Lamping KG, Kanatsuka H, Eastham CL, Chilian WM, and
Marcus ML. Nonuniform vasomotor responses of the coronary
microcirculation to serotonin and vasopressin. Circ Res 65: 343–
351, 1989.
Laxminarayan S, Sipkema P, and Westerhof N. Characterization of the arterial system in the time domain. IEEE Trans Biomed
Eng 25: 177–184, 1978.
Lazt L and Muller A. Pressure and velocity conditions in coronary
circulation in dogs. Helv Physiol Pharmacol Acta 15: 38 –54, 1957.
Levy BI, Duriez M, and Samuel JL. Coronary microvasculature
alteration in hypertensive rats. Effect of treatment with a diuretic
and an ACE inhibitor. Am J Hypertens 14: 7–13, 2001.
Li A, Li Z, Qu Z, Wang X, Xu B, Yu J, and Tian J. A new
echocardiographic system for assessment of epicardial and intramyocardial coronary flow in a swine model. Chin Med J 115:
1889 –1891, 2002.
Li K, Rouleau JL, Andries LJ, and Brutsaert DL. Effect of
dysfunctional vascular endothelium on myocardial performance in
isolated papillary muscles. Circ Res 72: 768 –777, 1993.
Lipscomb K and Gould KL. Mechanism of the effect of coronary
artery stenosis on coronary flow in the dog. Am Heart J 89: 60 – 67,
1975.
Livingston JZ, Halperin HR, and Yin FC. Accounting for the
Gregg effect in tetanised coronary arterial pressure-flow relationships. Cardiovasc Res 28: 228 –234, 1994.
Livingston JZ, Resar JR, and Yin FC. Effect of tetanic myocardial contraction on coronary pressure-flow relationships. Am J
Physiol Heart Circ Physiol 265: H1215–H1226, 1993.
Lunkenheimer PP, Redmann K, Florek J, Fassnacht U, Cryer
CW, Wubbeling F, Niederer P, and Anderson RH. The forces
generated within the musculature of the left ventricular wall. Heart
90: 200 –207, 2004.
MacCarthy P, Berger A, Manoharan G, Bartunek J, Barbato
E, Wijns W, Heyndrickx GR, Pijls NH, and De Bruyne B.
Pressure-derived measurement of coronary flow reserve. J Am Coll
Cardiol 45: 216 –220, 2005.
MacKenna DA, Omens JH, McCulloch AD, and Covell JW.
Contribution of collagen matrix to passive left ventricular mechanics in isolated rat hearts. Am J Physiol Heart Circ Physiol 266:
H1007–H1018, 1994.
Mao S, Lu B, Oudiz RJ, Bakhsheshi H, Liu SC, and Budoff MJ.
Coronary artery motion in electron beam tomography. J Comput
Assist Tomogr 24: 253–258, 2000.
Marcus JT, Smeenk HG, Kuijer JP, Van der Geest RJ,
Heethaar RM, and van Rossum AC. Flow profiles in the left
anterior descending and the right coronary artery assessed by MR
velocity quantification: effects of through-plane and in-plane motion of the heart. J Comput Assist Tomogr 23: 567–576, 1999.
Marcus ML, Chilian WM, Kanatsuka H, Dellsperger KC, Eastham CL, and Lamping KG. Understanding the coronary circulation through studies at the microvascular level. Circulation 82: 1–7,
1990.
Marques KM, Spruijt HJ, Boer C, Westerhof N, Visser CA, and
Visser FC. The diastolic flow-pressure gradient relation in coronary stenoses in humans. J Am Coll Cardiol 39: 1630 –1636, 2002.
Mates RE, Gupta RL, Bell AC, and Klocke FJ. Fluid dynamics
of coronary artery stenosis. Circ Res 42: 152–162, 1978.
Mates RE and Judd RM. Models for coronary pressure-flow relationships. Adv Exp Med Biol 346: 153–161, 1993.
Mates RE, Klocke FJ, and Canty JM Jr. Coronary capacitance.
Prog Cardiovasc Dis 31: 1–15, 1988.
Matsubara LS, Matsubara BB, Okoshi MP, Cicogna AC, and
Janicki JS. Alterations in myocardial collagen content affect rat
papillary muscle function. Am J Physiol Heart Circ Physiol 279:
H1534 –H1539, 2000.
Matsumoto T, Tachibana H, Asano T, Takemoto M, Ogasawara Y, Umetani K, and Kajiya F. Pattern differences between
distributions of microregional myocardial flows in crystalloid- and
86 • OCTOBER 2006 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017
241. Koller A and Bagi Z. Nitric oxide and H2O2 contribute to reactive
dilation of isolated coronary arterioles. Am J Physiol Heart Circ
Physiol 287: H2461–H2467, 2004.
242. Koller A and Kaley G. Endothelial regulation of wall shear stress
and blood flow in skeletal muscle microcirculation. Am J Physiol
Heart Circ Physiol 260: H862–H868, 1991.
243. Kouwenhoven E, Vergroesen I, Han Y, and Spaan JA. Retrograde coronary flow is limited by time-varying elastance. Am J
Physiol Heart Circ Physiol 263: H484 –H490, 1992.
244. Kovacs EJ and DiPietro LA. Fibrogenic cytokines and connective tissue production. FASEB J 8: 854 – 861, 1994.
245. Krams R, Sipkema P, and Westerhof N. Varying elastance concept may explain coronary systolic flow impediment. Am J Physiol
Heart Circ Physiol 257: H1471–H1479, 1989.
246. Krams R, Sipkema P, and Westerhof N. Coronary oscillatory
flow amplitude is more affected by perfusion pressure than ventricular pressure. Am J Physiol Heart Circ Physiol 258: H1889 –
H1898, 1990.
247. Krams R, Sipkema P, Zegers J, and Westerhof N. Contractility
is the main determinant of coronary systolic flow impediment.
Am J Physiol Heart Circ Physiol 257: H1936 –H1944, 1989.
248. Krams R, Ten Cate FJ, Carlier SG, Van Der Steen AF, and
Serruys PW. Diastolic coronary vascular reserve: a new index to
detect changes in the coronary microcirculation in hypertrophic
cardiomyopathy. J Am Coll Cardiol 43: 670 – 677, 2004.
249. Krams R, van Haelst AC, Sipkema P, and Westerhof N. Can
coronary systolic-diastolic flow differences be predicted by left
ventricular pressure or time-varying intramyocardial elastance?
Basic Res Cardiol 84: 149 –159, 1989.
250. Kresh JY. Intramyocardial mechanical states: vessel-interstitiummuscle interface. Adv Exp Med Biol 346: 113–123, 1993.
251. Kresh JY, Cobanoglu MA, and Brockman SK. The intramyocardial pressure: a parameter of heart contractility. J Heart Transplant 4: 241–246, 1985.
252. Kuikka JT. Effect of flow and vascular heterogeneity on glucose
metabolism in isolated dog hearts. Clin Physiol Funct Imaging 22:
134 –138, 2002.
253. Kuo L, Arko F, Chilian WM, and Davis MJ. Coronary venular
responses to flow and pressure. Circ Res 72: 607– 615, 1993.
254. Kuo L, Chilian WM, and Davis MJ. Coronary arteriolar myogenic
response is independent of endothelium. Circ Res 66: 860 – 866,
1990.
255. Kuo L, Chilian WM, and Davis MJ. Interaction of pressure- and
flow-induced responses in porcine coronary resistance vessels.
Am J Physiol Heart Circ Physiol 261: H1706 –H1715, 1991.
256. Kuo L, Davis MJ, and Chilian WM. Myogenic activity in isolated
subepicardial and subendocardial coronary arterioles. Am J
Physiol Heart Circ Physiol 255: H1558 –H1562, 1988.
257. Kuo L, Davis MJ, and Chilian WM. Endothelium-dependent,
flow-induced dilation of isolated coronary arterioles. Am J Physiol
Heart Circ Physiol 259: H1063–H1070, 1990.
258. Kyriakides ZS, Kolettis TM, Popov T, Mesiskli T, Triantafillou K, and Kremastinos DT. Coronary blood flow changes during
atrioventricular sequential pacing with different atrioventricular
delays in normal individuals. J Interv Card Electrophysiol 2: 163–
169, 1998.
259. L’Abbate A, Camici P, Trivella MG, Pelosi G, Davies GJ,
Ballestra AM, and Taddei L. Time-dependent response of coronary flow to prolonged adenosine infusion: doubling of peak reactive hyperaemic flow. Cardiovasc Res 15: 282–286, 1981.
260. Lader AS, Smith RS, Phillips GC, McNamee JE, and Abel FL.
Distribution of coronary arterial capacitance in a canine model.
J Appl Physiol 84: 954 –962, 1998.
261. Lamberts RR, Van Rijen MH, Sipkema P, Fransen P, Sys SU,
and Westerhof N. Coronary perfusion and muscle lengthening
increase cardiac contraction: different stretch-triggered mechanisms. Am J Physiol Heart Circ Physiol 283: H1515–H1522, 2002.
262. Lamberts RR, Van Rijen MH, Sipkema P, Fransen P, Sys SU,
and Westerhof N. Increased coronary perfusion augments cardiac
contractility in the rat through stretch-activated ion channels. Am J
Physiol Heart Circ Physiol 282: H1334 –H1340, 2002.
263. Lamberts RR, Willemsen MJ, Perez NG, Sipkema P, and
Westerhof N. Acute and specific collagen type I degradation in-
1303
1304
286.
287.
288.
289.
290.
292.
293.
294.
295.
296.
297.
298.
299.
300.
301.
302.
303.
304.
305.
blood-perfused rat hearts. Am J Physiol Heart Circ Physiol 286:
H1331–H1338, 2004.
Matsuoka S, Kanazawa S, Ogasawara Y, Goto M, Hiramatsu
O, Tsujioka K, Fujiwara T, and Kajiya F. Characteristics of
blood flow velocity waveforms and profiles in the human normal
coronary artery. Proc Int Conf Satellite Symp Cardiovasc Syst
Dynamics Soc 9th Halifax Nova Scotia 1988, p. 121–124.
May-Newman K, Omens JH, Pavelec RS, and McCulloch AD.
Three-dimensional transmural mechanical interaction between the
coronary vasculature and passive myocardium in the dog. Circ Res
74: 1166 –1178, 1994.
Mazhari R, Omens JH, Pavelec RS, Covell JW, and McCulloch
AD. Transmural distribution of three-dimensional systolic strains
in stunned myocardium. Circulation 104: 336 –341, 2001.
McCulloch AD, Hunter PJ, and Smaill BH. Mechanical effects of
coronary perfusion in the passive canine left ventricle. Am J
Physiol Heart Circ Physiol 262: H523–H530, 1992.
McCulloch AD, Sung D, Wilson JM, Pavelec RS, and Omens
JH. Flow-function relations during graded coronary occlusions in
the dog: effects of transmural location and segment orientation.
Cardiovasc Res 37: 636 – 645, 1998.
McKeever WP, Gregg DE, and Canney PC. Oxygen uptake of the
nonworking left ventricle. Circ Res 6: 612– 623, 1958.
Meier J, Kleen M, and Messmer K. A computer model of fractal
myocardial perfusion heterogeneity to elucidate mechanisms of
changes in critical coronary stenosis and hypotension. Bull Math
Biol 66: 1155–1171, 2004.
Merkus D, Chilian WM, and Stepp DW. Functional characteristics of the coronary microcirculation. Herz 24: 496 –508, 1999.
Merkus D, Duncker DJ, and Chilian WM. Metabolic regulation
of coronary vascular tone: role of endothelin-1. Am J Physiol Heart
Circ Physiol 283: H1915–H1921, 2002.
Merkus D, Kajiya F, Vink H, Vergroesen I, Dankelman J, Goto
M, and Spaan JA. Prolonged diastolic time fraction protects myocardial perfusion when coronary blood flow is reduced. Circulation 100: 75– 81, 1999.
Merkus D, Vergroesen I, Hiramatsu O, Tachibana H, Nakamoto H, Toyota E, Goto M, Ogasawara Y, Spaan JA, and
Kajiya F. Stenosis differentially affects subendocardial and subepicardial arterioles in vivo. Am J Physiol Heart Circ Physiol 280:
H1674 –H1682, 2001.
Mihailescu LS and Abel FL. Intramyocardial pressure gradients
in working and nonworking isolated cat hearts. Am J Physiol Heart
Circ Physiol 266: H1233–H1241, 1994.
Miller FJ Jr, Dellsperger KC, and Gutterman DD. Myogenic
constriction of human coronary arterioles. Am J Physiol Heart
Circ Physiol 273: H257–H264, 1997.
Miller WP, Nellis SH, Liedtke AJ, Whitesell L, and Effron BA.
Coronary hyperperfusion and ventricular function in intact and
isovolumic pig hearts. Am J Physiol Heart Circ Physiol 258: H500 –
H507, 1990.
Misawa K, Nitta Y, Matsubara T, Oe K, Kiyama M, Shimizu M,
and Mabuchi H. Difference in coronary blood flow dynamics
between patients with hypertension and those with hypertrophic
cardiomyopathy. Hypertens Res 25: 711–716, 2002.
Mitsugi M, Saito T, Saitoh S, Sato M, and Maruyama Y. Effects
of synchronized retroperfusion on the coronary arterial pressureflow relationship. Cardiovasc Res 32: 335–343, 1996.
Mitsugi M, Saito T, Sato M, Saitoh S, Niitsuma T, Maehara K,
and Maruyama Y. Effects of cardiac contraction and increased
coronary sinus pressure on the coronary arterial pressure-flow
relationship. Jpn Heart J 40: 339 –350, 1999.
Miura T, Hiramatsu T, Forbess JM, and Mayer JE Jr. Effects
of elevated coronary sinus pressure on coronary blood flow and
left ventricular function. Implications after the Fontan operation.
Circulation 92: II298 –II303, 1995.
Morgenstern C, Holjes U, Arnold G, and Lochner W. The
influence of coronary pressure and coronary flow on intracoronary
blood volume and geometry of the left ventricle. Pflügers Arch 340:
101–111, 1973.
Mori H, Tanaka E, Hyodo K, Uddin MM, Sekka T, Ito K,
Shinozaki Y, Tanaka A, Nakazawa H, Abe S, Handa S, Kubota
M, Tanioka K, Umetani K, and Ando M. Synchrotron microanPhysiol Rev • VOL
306.
307.
308.
309.
310.
311.
312.
313.
314.
315.
316.
317.
318.
319.
320.
321.
322.
323.
324.
325.
326.
giography reveals configurational changes and to-and-fro flow in
intramyocardial vessels. Am J Physiol Heart Circ Physiol 276:
H429 –H437, 1999.
Mosher P, Ross J Jr, McFate PA, and Shaw RF. Control of
coronary blood flow by an autoregulatory mechanism. Circ Res 14:
250 –259, 1964.
Nanto S, Masuyama T, Takano Y, Hori M, and Nagata S.
Determination of coronary zero flow pressure by analysis of the
baseline pressure-flow relationship in humans. Jpn Circ J 65: 793–
796, 2001.
Neagoe C, Opitz CA, Makarenko I, and Linke WA. Gigantic
variety: expression patterns of titin isoforms in striated muscles
and consequences for myofibrillar passive stiffness. J Muscle Res
Cell Motil 24: 175–189, 2003.
Nematzadeh D, Rose JC, Schryver T, Huang HK, and Kot PA.
Analysis of methodology for measurement of intramyocardial pressure. Basic Res Cardiol 79: 86 –97, 1984.
Newman DL, Westerhof N, and Sipkema P. Modelling of aortic
stenosis. J Biomech 12: 229 –235, 1979.
O’Brien LJ and Moore CM. Connective tissue degradation and
distensibility characteristics of the non-living heart. Experientia
22: 845– 847, 1966.
Ohayon J and Chadwick RS. Effects of collagen microstructure
on the mechanics of the left ventricle. Biophys J 54: 1077–1088,
1988.
Olsen CO, Attarian DE, Jones RN, Hill RC, Sink JD, Lee KL,
and Wechsler AS. The coronary pressure-flow determinants left
ventricular compliance in dogs. Circ Res 49: 856 – 865, 1981.
Olsson RA and Bugni WJ. The coronary circulation. In: The Heart
and Cardiovascular System: Scientific Foundations, edited by
Fozzard HE, Haber E, Jennings RB, Katz AM, and Morgan HE. New
York: Raven, 1986, p. 987–107.
O’Rourke MF. Ascending aortic pressure wave indices and cardiovascular disease. Am J Hypertens 17: 721–723, 2004.
Pagliaro P, Chiribiri A, Gattullo D, Penna C, Rastaldo R, and
Recchia FA. Fatty acids are important for the Frank-Starling
mechanism and Gregg effect but not for catecholamine response in
isolated rat hearts. Acta Physiol Scand 176: 167–176, 2002.
Pagliaro P, Gattullo D, Linden RJ, Losano G, and Westerhof
N. Systolic coronary flow impediment in the dog: role of ventricular
pressure and contractility. Exp Physiol 83: 821– 831, 1998.
Perktold K, Hofer M, Rappitsch G, Loew M, Kuban BD, and
Friedman MH. Validated computation of physiologic flow in a
realistic coronary artery branch. J Biomech 31: 217–228, 1998.
Petropoulakis PN, Kyriakidis MK, Tentolouris CA, Kourouclis CV, and Toutouzas PK. Changes in phasic coronary blood
flow velocity profile in relation to changes in hemodynamic parameters during stress in patients with aortic valve stenosis. Circulation 92: 1437–1447, 1995.
Pijls NH and De Bruyne B. Coronary Pressure. Dordrecht: Kluwer Academic, 2000.
Piuhola J, Makinen M, Szokodi I, and Ruskoaho H. Dual role of
endothelin-1 via ETA and ETB receptors in regulation of cardiac
contractile function in mice. Am J Physiol Heart Circ Physiol 285:
H112–H118, 2003.
Poche R, Arnold G, and Gahlen D. The influence of coronary
perfusion pressure on metabolism and ultrastructure of the myocardium of the arrested aerobically perfused isolated guinea-pig
heart. Virchows Arch B Cell Pathol 8: 252–266, 1971.
Popp R, Fleming I, and Busse R. Pulsatile stretch in coronary
arteries elicits release of endothelium-derived hyperpolarizing factor: a modulator of arterial compliance. Circ Res 82: 696 –703, 1998.
Pries AR, Schonfeld D, Gaehtgens P, Kiani MF, and Cokelet
GR. Diameter variability and microvascular flow resistance. Am J
Physiol Heart Circ Physiol 272: H2716 –H2725, 1997.
Pries AR, Secomb TW, Jacobs H, Sperandio M, Osterloh K,
and Gaehtgens P. Microvascular blood flow resistance: role of
endothelial surface layer. Am J Physiol Heart Circ Physiol 273:
H2272–H2279, 1997.
Prosi M, Perktold K, Ding Z, and Friedman MH. Influence of
curvature dynamics on pulsatile coronary artery flow in a realistic
bifurcation model. J Biomech 37: 1767–1775, 2004.
86 • OCTOBER 2006 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017
291.
WESTERHOF ET AL.
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
Physiol Rev • VOL
349.
350.
351.
352.
353.
354.
355.
356.
357.
358.
359.
360.
361.
362.
363.
364.
365.
366.
367.
368.
369.
pressure in transiently arrested heart. Cardiovasc Res 24: 358 –363,
1990.
Schanzenbacher P and Klocke FJ. Measurement of heterogeneous myocardial blood flow. Clin Cardiol 3: 51–53, 1980.
Scharf SM and Bromberger-Barnea B. Influence of coronary
flow and pressure on cardiac function and coronary vascular volume. Am J Physiol 224: 918 –925, 1973.
Schipke JD, Stocks I, Sunderdiek U, and Arnold G. Effect of
changes in aortic pressure and in coronary arterial pressure on left
ventricular geometry and function Anrep vs. gardenhose effect.
Basic Res Cardiol 88: 621– 637, 1993.
Schmid-Schonbein H. Critical closing pressure or yield shear
stress as the cause of disturbed peripheral circulation? Acta Chir
Scand Suppl 465: 10 –19, 1976.
Schouten VJ, Allaart CP, and Westerhof N. Effect of perfusion
pressure on force of contraction in thin papillary muscles and
trabeculae from rat heart. J Physiol 451: 585– 604, 1992.
Schouten VJ and ter Keurs HE. Role of ICa and Na⫹/Ca2⫹
exchange in the force-frequency relationship of rat heart muscle. J
Mol Cell Cardiol 23: 1039 –1050, 1991.
Schulz R, Guth BD, and Heusch G. No effect of coronary perfusion on regional myocardial function within the autoregulatory
range in pigs. Evidence against the Gregg phenomenon. Circulation 83: 1390 –1403, 1991.
Schwartz GG, Schaefer S, Trocha SD, Garcia J, Steinman S,
Massie BM, and Weiner MW. Effect of supranormal coronary
blood flow on energy metabolism and systolic function of porcine
left ventricle. Cardiovasc Res 26: 1001–1006, 1992.
Segal SS and Duling BR. Flow control among microvessels coordinated by intercellular conduction. Science 234: 868 – 870, 1986.
Sherman IA. Interfacial tension effects in the microvasculature.
Microvasc Res 22: 296 –307, 1981.
Sherman IA and Grayson J. Function of the coronary arterial
collateral network in healthy myocardium: studies of peripheral
coronary pressure in the dog. Can J Physiol Pharmacol 58: 134 –
140, 1980.
Shimada T, Kitamura H, and Nakamura M. Three-dimensional
architecture of pericytes with special reference to their topographical relationship to microvascular beds. Arch Histol Cytol 55 Suppl:
77– 85, 1992.
Siebes M, Chamuleau SA, Meuwissen M, Piek JJ, and Spaan
JA. Influence of hemodynamic conditions on fractional flow reserve: parametric analysis of underlying model. Am J Physiol
Heart Circ Physiol 283: H1462–H1470, 2002.
Sipkema P, Takkenberg JJ, Zeeuwe PE, and Westerhof N. Left
coronary pressure-flow relations of the beating and arrested rabbit
heart at different ventricular volumes. Cardiovasc Res 40: 88 –95,
1998.
Sipkema P, Van Der Linden PJ, Westerhof N, and Yin FC.
Effect of cyclic axial stretch of rat arteries on endothelial cytoskeletal morphology and vascular reactivity. J Biomech 36: 653– 659,
2003.
Sipkema P and Westerhof N. Mechanics of a thin walled collapsible microtube. Ann Biomed Eng 17: 203–217, 1989.
Sipkema P, Westerhof N, and Hoogerwerf N. Rate of the myogenic response increases with the constriction level in rabbit femoral arteries. Ann Biomed Eng 25: 278 –285, 1997.
Sipkema P, Westerhof N, and Randall OS. The arterial system
characterised in the time domain. Cardiovasc Res 14: 270 –279,
1980.
Skalidis EI, Kochiadakis GE, Igoumenidis NE, Vardakis KE,
and Vardas PE. Phasic coronary blood flow velocity pattern and
flow reserve in the atrium: regulation of left atrial myocardial
perfusion. J Am Coll Cardiol 41: 674 – 680, 2003.
Skalidis EI, Kochiadakis GE, Koukouraki SI, Parthenakis FI,
Karkavitsas NS, and Vardas PE. Phasic coronary flow pattern
and flow reserve in patients with left bundle branch block and
normal coronary arteries. J Am Coll Cardiol 33: 1338 –1346, 1999.
Smith NP. A computational study of the interaction between coronary blood flow and myocardial mechanics. Physiol Meas 25:
863– 877, 2004.
86 • OCTOBER 2006 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017
327. Rabbany SY, Kresh JY, and Noordergraaf A. Intramyocardial
pressure: interaction of myocardial fluid pressure and fiber stress.
Am J Physiol Heart Circ Physiol 257: H357–H364, 1989.
328. Rajappan K, Rimoldi OE, Camici PG, Bellenger NG, Pennell
DJ, and Sheridan DJ. Functional changes in coronary microcirculation after valve replacement in patients with aortic stenosis.
Circulation 107: 3170 –3175, 2003.
329. Ramaciotti C, McClellan G, Sharkey A, Rose D, Weisberg A,
and Winegrad S. Cardiac endothelial cells modulate contractility
of rat heart in response to oxygen tension and coronary flow. Circ
Res 72: 1044 –1064, 1993.
330. Ramaciotti C, Sharkey A, McClellan G, and Winegrad S. Endothelial cells regulate cardiac contractility. Proc Natl Acad Sci
USA 89: 4033– 4036, 1992.
331. Ratajska A, Ciszek B, and Sowinska A. Embryonic development
of coronary vasculature in rats: corrosion casting studies. Anat Rec
A Discov Mol Cell Evol Biol 270: 109 –116, 2003.
332. Recchia FA, Senzaki H, Saeki A, Byrne BJ, and Kass DA. Pulse
pressure-related changes in coronary flow in vivo are modulated by
nitric oxide and adenosine. Circ Res 79: 849 – 856, 1996.
333. Resar J, Livingston JZ, Halperin HR, Sipkema P, Krams R,
and Yin FC. Effect of wall stretch on coronary hemodynamics in
isolated canine interventricular septum. Am J Physiol Heart Circ
Physiol 259: H1869 –H1880, 1990.
334. Resar JR, Judd RM, Halperin HR, Chacko VP, Weiss RG, and
Yin FC. Direct evidence that coronary perfusion affects diastolic
myocardial mechanical properties in canine heart. Cardiovasc Res
27: 403– 410, 1993.
335. Rhodin JA. The ultrastructure of mammalian arterioles and precapillary sphincters. J Ultrastruct Res 18: 181–223, 1967.
336. Ritman EL. In vivo myocardial microcirculation: evaluation with a
whole-body x-ray CT method. Adv Exp Med Biol 346: 163–171,
1993.
337. Rooke GA and Feigl EO. Work as a correlate of canine left
ventricular oxygen consumption, and the problem of catecholamine oxygen wasting. Circ Res 50: 273–286, 1982.
338. Rouleau J, Boerboom LE, Surjadhana A, and Hoffman JI. The
role of autoregulation and tissue diastolic pressures in the transmural distribution of left ventricular blood flow in anesthetized
dogs. Circ Res 45: 804 – 815, 1979.
339. Rouleau JR and White M. Effects of coronary sinus pressure
elevation on coronary blood flow distribution in dogs with normal
preload. Can J Physiol Pharmacol 63: 787–797, 1985.
340. Rubio R and Ceballos G. Role of the endothelial glycocalyx in
dromotropic, inotropic, and arrythmogenic effects of coronary
flow. Am J Physiol Heart Circ Physiol 278: H106 –H116, 2000.
341. Ruiter JH, Spaan JA, and Laird JD. Transient oxygen uptake
during myocardial reactive hyperemia in the dog. Am J Physiol
Heart Circ Physiol 235: H87–H94, 1978.
342. Sagawa K and Eisner A. Static pressure-flow relation in the total
systemic vascular bed of the dog and its modification by the
baroreceptor reflex. Circ Res 36: 406 – 413, 1975.
343. Salisbury PF, Cross CE, and Rieben PA. Influence of coronary
artery pressure upon myocardial elasticity. Circ Res 8: 794 – 800,
1960.
344. Sambuceti G, Marzilli M, Mari A, Marini C, Schluter M, Testa
R, Papini M, Marraccini P, Ciriello G, Marzullo P, and
L’Abbate A. Coronary microcirculatory vasoconstriction is heterogeneously distributed in acutely ischemic myocardium. Am J
Physiol Heart Circ Physiol 288: H2298 –H2305, 2005.
345. Sarnoff SJ, Braunwald E, Welch GH Jr, Case RB, Stainsby
WN, and Macruz R. Hemodynamic determinants of oxygen consumption of the heart with special reference to the tension-time
index. Am J Physiol 192: 148 –156, 1958.
346. Sato M, Saito T, Mitsugi M, Saitoh S, Niitsuma T, Maehara K,
and Maruyama Y. Effects of cardiac contraction and coronary
sinus pressure elevation on collateral circulation. Am J Physiol
Heart Circ Physiol 271: H1433–H1440, 1996.
347. Satoh S, Klocke FJ, and Canty JM Jr. Tone-dependent coronary
arterial-venous pressure differences at the cessation of venous
outflow during long diastoles. Circulation 88: 1238 –1244, 1993.
348. Satoh S, Maruyama Y, Watanabe J, Keitoku M, Hangai K, and
Takishima T. Coronary zero flow pressure and intramyocardial
1305
1306
WESTERHOF ET AL.
Physiol Rev • VOL
392. Susic D, Varagic J, Ahn J, and Frohlich ED. Cardiovascular and
renal effects of a collagen cross-link breaker (ALT 711) in adult and
aged spontaneously hypertensive rats. Am J Hypertens 17: 328 –
333, 2004.
393. Tadaoka S, Kimura A, Yada T, Tsujioka K, Nezuo S,
Sawayama T, and Kajiya F. Decreased mid-to-late diastolic decay
of diastolic coronary artery flow velocity in pressure-overloaded
left ventricular hypertrophy. Heart Vessels 8: 91–97, 1993.
394. Tadaoka S, Wada Y, Kimura A, Yada T, Tamura K, Hasegawa
K, Nezuo S, Sawayama T, Tsujioka K, and Kajiya F. Effect of
left ventricular hypertrophy secondary to systemic hypertension on
left coronary artery flow dynamics. Cardiovasc Res 25: 955–964,
1991.
395. Taira N, Himori N, and Imai Y. Inhibition of excitation-contraction coupling in the ventricular myocardium of the dog by SKF
24260. Clin Exp Pharmacol Physiol 3: 567–574, 1976.
396. Takahashi S, Barry AC, and Factor SM. Collagen degradation in
ischaemic rat hearts. Biochem J 265: 233–241, 1990.
397. Tamborini G, Maltagliati A, Trupiano L, Berna G, Sisillo E,
Salvi L, and Pepi M. Lowering of blood pressure and coronary
blood flow in isolated systolic hypertension. Coronary Artery Dis
12: 259 –265, 2001.
398. Templeton GH, Wildenthal K, and Mitchell JH. Influence of
coronary blood flow on left ventricular contractility and stiffness.
Am J Physiol 223: 1216 –1220, 1972.
399. Terracio L, Rubin K, Gullberg D, Balog E, Carver W, Jyring R,
and Borg TK. Expression of collagen binding integrins during
cardiac development and hypertrophy. Circ Res 68: 734 –744, 1991.
400. Tiefenbacher CP and Chilian WM. Heterogeneity of coronary
vasomotion. Basic Res Cardiol 93: 446 – 454, 1998.
401. Tillmanns H, Ikeda S, Hansen H, Sarma JS, Fauvel JM, and
Bing RJ. Microcirculation in the ventricle of the dog and turtle.
Circ Res 34: 561–569, 1974.
402. Tillmanns H, Steinhausen M, Leinberger H, Thederan H, and
Kubler W. Pressure measurements in the terminal vascular bed of
the epimyocardium of rats and cats. Circ Res 49: 1202–1211, 1981.
403. Todaka K, Jiang T, Chapman JT, Gu A, Zhu SM, Herzog E,
Hochman JS, Steinberg SF, and Burkhoff D. Functional consequences of acute collagen degradation studied in crystalloid perfused rat hearts. Basic Res Cardiol 92: 147–158, 1997.
404. Tomanek RJ and Zheng W. Role of growth factors in coronary
morphogenesis. Tex Heart Inst J 29: 250 –254, 2002.
405. Toyota E, Fujimoto K, Ogasawara Y, Kajita T, Shigeto F,
Matsumoto T, Goto M, and Kajiya F. Dynamic changes in threedimensional architecture and vascular volume of transmural coronary microvasculature between diastolic- and systolic-arrested rat
hearts. Circulation 105: 621– 626, 2002.
406. Toyota E, Ogasawara Y, Hiramatsu O, Tachibana H, Kajiya F,
Yamamori S, and Chilian WM. Dynamics of flow velocities in
endocardial and epicardial coronary arterioles. Am J Physiol Heart
Circ Physiol 288: H1598 –H1603, 2005.
407. Tsujioka K, Goto M, Hiramatsu O, Wada Y, Ogasawara Y, and
Kajiya F. Functional characteristics of intramyocardial capacitance vessels and their effects on coronary arterial inflow and
venous outflow. In: Coronary Circulation: Basic Mechanisms and
Clinical Relevance, edited by Kajiya F, Klassen GA, Spaan JA, and
Hoffman JI. Tokyo: Springer-Verlag, 1990.
408. Tune JD, Gorman MW, and Feigl EO. Matching coronary blood
flow to myocardial oxygen consumption. J Appl Physiol 97: 404 –
415, 2004.
409. Uhlig PN, Baer RW, Vlahakes GJ, Hanley FL, Messina LM, and
Hoffman JI. Arterial and venous coronary pressure-flow relations
in anesthetized dogs. Evidence for a vascular waterfall in epicardial
coronary veins. Circ Res 55: 238 –248, 1984.
409a.VanBavel E and Spaan JA. Branching patterns in the porcine
coronary arterial tree. Estimation of flow heterogeneity. Circ Res
71: 1200 –1212, 1992.
410. Van Beek JH, Barends JP, and Westerhof N. The microvascular
unit size for fractal flow heterogeneity relevant for oxygen transport. Adv Exp Med Biol 345: 901–908, 1994.
411. Van der Ploeg CP, Dankelman J, and Spaan JA. Functional
distribution of coronary vascular volume in beating goat hearts.
Am J Physiol Heart Circ Physiol 264: H770 –H776, 1993.
86 • OCTOBER 2006 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017
370. Smith NP and Kassab GS. Analysis of coronary blood flow interaction with myocaridal mechanics based on anatomical models.
Philos Trans R Soc Lond A 359: 1251–1263, 2001.
371. Smith NP, Pullan AJ, and Hunter PJ. Generation of an anatomically based geometric coronary model. Ann Biomed Eng 28: 14 –
25, 2000.
372. Sonntag M, Deussen A, Schultz J, Loncar R, Hort W, and
Schrader J. Spatial heterogeneity of blood flow in the dog heart. I.
Glucose uptake, free adenosine and oxidative/glycolytic enzyme
activity. Pflügers Arch 432: 439 – 450, 1996.
373. Sorop O, Spaan JA, Sweeney TE, and VanBavel E. Effect of
steady versus oscillating flow on porcine coronary arterioles: involvement of NO and superoxide anion. Circ Res 92: 1344 –1351,
2003.
374. Sorop O, Spaan JA, and VanBavel E. Pulsation-induced dilation
of subendocardial and subepicardial arterioles: effect on vasodilator sensitivity. Am J Physiol Heart Circ Physiol 282: H311–H319,
2002.
375. Spaan JA. Coronary diastolic pressure-flow relation and zero flow
pressure explained on the basis of intramyocardial compliance.
Circ Res 56: 293–309, 1985.
376. Spaan JA. Coronary Blood Flow. Mechanics, Distribution and
Control. Dordrecht: Kluwer Academic, 1991.
377. Spaan JA. Mechanical determinants of myocardial perfusion. Basic Res Cardiol 90: 89 –102, 1995.
378. Spaan JA, Breuls NP, and Laird JD. Diastolic-systolic coronary
flow differences are caused by intramyocardial pump action in the
anesthetized dog. Circ Res 49: 584 –593, 1981.
379. Spaan JA, Breuls NP, and Laird JD. Forward coronary flow
normally seen in systole is the result of both forward and concealed
back flow. Basic Res Cardiol 76: 582–586, 1981.
380. Spaan JA, Cornelissen AJ, Chan C, Dankelman J, and Yin FC.
Dynamics of flow, resistance, and intramural vascular volume in
canine coronary circulation. Am J Physiol Heart Circ Physiol 278:
H383–H403, 2000.
381. Spaan JA, ter Wee R, van Teeffelen JW, Streekstra G, Siebes
M, Kolyva C, Vink H, Fokkema DS, and VanBavel E. Visualisation of intramural coronary vasculature by an imaging cryomicrotome suggests compartmentalisation of myocardial perfusion
areas. Med Biol Eng Comput 43: 431– 435, 2005.
382. Stahl LD, Aversano TR, and Becker LC. Selective enhancement
of function of stunned myocardium by increased flow. Circulation
74: 843– 851, 1986.
383. Streeter DD Jr, Spotnitz HM, Patel DP, Ross J Jr, and Sonnenblick EH. Fiber orientation in the canine left ventricle during
diastole and systole. Circ Res 24: 339 –347, 1969.
384. Stroud JD, Baicu CF, Barnes MA, Spinale FG, and Zile MR.
Viscoelastic properties of pressure overload hypertrophied myocardium: effect of serine protease treatment. Am J Physiol Heart
Circ Physiol 282: H2324 –H2335, 2002.
385. Suarez J, Torres C, Sanchez L, del Valle L, and Pastelin G.
Flow stimulates nitric oxide release in guinea pig heart: role of
stretch-activated ion channels. Biochem Biophys Res Commun
261: 6 –9, 1999.
386. Suga H. Ventricular energetics. Physiol Rev 70: 247–277, 1990.
387. Suga H, Sagawa K, and Shoukas AA. Load independence of the
instantaneous pressure-volume ratio of the canine left ventricle
and effects of epinephrine and heart rate on the ratio. Circ Res 32:
314 –322, 1973.
388. Sun D, Huang A, and Kaley G. Mechanical compression elicits
NO-dependent increases in coronary flow. Am J Physiol Heart Circ
Physiol 287: H2454 –H2460, 2004.
389. Sun YH, Anderson TJ, Parker KH, and Tyberg JV. Wave-intensity analysis: a new approach to coronary hemodynamics. J Appl
Physiol 89: 1636 –1644, 2000.
390. Sun YH, Anderson TJ, Parker KH, and Tyberg JV. Effects of
left ventricular contractility and coronary vascular resistance on
coronary dynamics. Am J Physiol Heart Circ Physiol 286: H1590 –
H1595, 2004.
391. Sunagawa K, Maughan WL, Friesinger G, Guzman P, Chang
MS, and Sagawa K. Effects of coronary arterial pressure on left
ventricular end-systolic pressure-volume relation of isolated canine
heart. Circ Res 50: 727–734, 1982.
CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE
Physiol Rev • VOL
433. Ward KE, Fisher DJ, and Michael L. Elevated coronary sinus
pressure does not alter myocardial blood flow or left ventricular
contractile function in mature sheep. Implications after the Fontan
operation. J Thorac Cardiovasc Surg 95: 511–515, 1988.
434. Watanabe J, Levine MJ, Bellotto F, Johnson RG, and Grossman W. Effects of coronary venous pressure on left ventricular
diastolic distensibility. Circ Res 67: 923–932, 1990.
435. Watanabe J, Levine MJ, Bellotto F, Johnson RG, and Grossman W. Left ventricular diastolic chamber stiffness and intramyocardial coronary capacitance in isolated dog hearts. Circulation
88: 2929 –2940, 1993.
436. Watanabe J, Maruyama Y, Satoh S, Keitoku M, and Takishima
T. Effects of the pericardium on the diastolic left coronary pressure-flow relationship in the isolated dog heart. Circulation 75:
670 – 675, 1987.
437. Weber KT. Cardiac interstitium in health and disease: the fibrillar
collagen network. J Am Coll Cardiol 13: 1637–1652, 1989.
438. Weber KT, Brilla CG, and Janicki JS. Myocardial fibrosis: functional significance and regulatory factors. Cardiovasc Res 27: 341–
348, 1993.
439. Weber KT, Pick R, Silver MA, Moe GW, Janicki JS, Zucker IH,
and Armstrong PW. Fibrillar collagen and remodeling of dilated
canine left ventricle. Circulation 82: 1387–1401, 1990.
440. Wei K, Le E, Jayaweera AR, Bin JP, Goodman NC, and Kaul S.
Detection of noncritical coronary stenosis at rest without recourse
to exercise or pharmacological stress. Circulation 105: 218 –223,
2002.
441. Weizsacker HW, Lambert H, and Pascale K. Analysis of the
passive mechanical properties of rat carotid arteries. J Biomech 16:
703–715, 1983.
442. Weizsacker HW and Pinto JG. Isotropy and anisotropy of the
arterial wall. J Biomech 21: 477– 487, 1988.
443. Westerhof N. Physiological hypotheses—intramyocardial pressure. A new concept, suggestions for measurement. Basic Res
Cardiol 85: 105–119, 1990.
444. Westerhof N, Elzinga G, and Sipkema P. An artificial arterial
system for pumping hearts. J Appl Physiol 31: 776 –781, 1971.
445. Westerhof N and Krams R. Comments on “Pressure and tone
dependence of coronary diastolic input impedance and capacitance.” Am J Physiol Heart Circ Physiol 250: H330 –H331, 1986.
446. Westerhof N, Sipkema P, and van Huis GA. Coronary pressureflow relations and the vascular waterfall. Cardiovasc Res 17: 162–
169, 1983.
447. Westerhof N, Sipkema P, and Vis MA. How cardiac contraction
affects the coronary vasculature. Adv Exp Med Biol 430: 111–121,
1997.
448. Westerhof N, Stergiopulos N, and Noble MI. Snapshots of
Hemodynamics. An Aid for Clinical Research and Graduate Education. Dordrecht: Kluwer Academic, 2004.
449. Wexler LF, Grice WN, Huntington M, Plehn JF, and Apstein
CS. Coronary hypertension and diastolic compliance in isolated
rabbit hearts. Hypertension 13: 598 – 606, 1989.
450. Willemsen MJ, Duncker DJ, Krams R, Dijkman MA, Lamberts
RR, Sipkema P, and Westerhof N. Decrease in coronary vascular
volume in systole augments cardiac contraction. Am J Physiol
Heart Circ Physiol 281: H731–H737, 2001.
451. Yada T, Hiramatsu O, Goto M, Ogasawara Y, Kimura A,
Yamamoto T, Tsujioka K, and Kajiya F. Effects of nitroglycerin
on diameter and pulsation amplitude of subendocardial arterioles
in beating porcine heart. Am J Physiol Heart Circ Physiol 267:
H1719 –H1725, 1994.
452. Yada T, Hiramatsu O, Kimura A, Goto M, Ogasawara Y, Tsujioka K, Yamamori S, Ohno K, Hosaka H, and Kajiya F. In vivo
observation of subendocardial microvessels of the beating porcine
heart using a needle-probe videomicroscope with a CCD camera.
Circ Res 72: 939 –946, 1993.
453. Yada T, Shimokawa H, Hiramatsu O, Kajita T, Shigeto F, Goto
M, Ogasawara Y, and Kajiya F. Hydrogen peroxide, an endogenous endothelium-derived hyperpolarizing factor, plays an important role in coronary autoregulation in vivo. Circulation 107: 1040 –
1045, 2003.
454. Yamamoto K, Ito H, Iwakura K, Kawano S, Ikushima M, Masuyama T, Ogihara T, and Fujii K. Two different coronary blood
86 • OCTOBER 2006 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017
412. Van der Ploeg CP, Dankelman J, and Spaan JA. Heart rate
affects the dependency of myocardial oxygen consumption on flow
in goats. Heart Vessels 10: 258 –265, 1995.
413. Van der Velden J, Klein LJ, Zaremba R, Boontje NM, Huybregts MA, Stooker W, Eijsman L, de Jong JW, Visser CA,
Visser FC, and Stienen GJ. Effects of calcium, inorganic phosphate, and pH on isometric force in single skinned cardiomyocytes
from donor and failing human hearts. Circulation 104: 1140 –1146,
2001.
414. Van der Vusse GJ, Arts T, Glatz JF, and Reneman RS. Transmural differences in energy metabolism of the left ventricular
myocardium: fact or fiction. J Mol Cell Cardiol 22: 23–37, 1990.
415. Van Dijk LC, Krams R, Sipkema P, and Westerhof N. Changes
in coronary pressure-flow relation after transition from blood to
Tyrode perfusion. Am J Physiol Heart Circ Physiol 255: H476 –
H482, 1988.
416. Van Huis GA, Sipkema P, and Westerhof N. Instantaneous and
steady-state pressure-flow relations of the coronary system in the
canine beating heart. Cardiovasc Res 19: 121–131, 1985.
417. Van Huis GA, Sipkema P, and Westerhof N. Coronary input
impedance during cardiac cycle as determined by impulse response method. Am J Physiol Heart Circ Physiol 253: H317–H324,
1987.
418. VanTeeffelen JW, Merkus D, Bos LJ, Vergroesen I, and Spaan
JA. Impairment of contraction increases sensitivity of epicardial
lymph pressure for left ventricular pressure. Am J Physiol Heart
Circ Physiol 274: H187–H192, 1998.
419. VanTeeffelen JW, Merkus D, Vergroesen I, and Spaan JA.
Changes in myocardial fluid filtration are reflected in epicardial
lymph pressure. Am J Physiol Heart Circ Physiol 272: H706 –H713,
1997.
420. Van Winkle DM, Swafford AN Jr, and Downey JM. Subendocardial coronary compression in beating dog hearts is independent
of pressure in the ventricular lumen. Am J Physiol Heart Circ
Physiol 261: H500 –H505, 1991.
422. Vergroesen I, Han Y, Goto M, and Spaan JA. Cardiac contraction and intramyocardial venous pressure generation in the anaesthetized dog. J Physiol 480: 343–353, 1994.
423. Vergroesen I, Noble MI, and Spaan JA. Intramyocardial blood
volume change in first moments of cardiac arrest in anesthetized
goats. Am J Physiol Heart Circ Physiol 253: H307–H316, 1987.
424. Versluis JP, Heslinga JW, Sipkema P, and Westerhof N. Microvascular pressure measurement reveals a coronary vascular
waterfall in arterioles larger than 110 micron. Am J Physiol Heart
Circ Physiol 281: H1913–H1918, 2001.
425. Vink H, Wieringa PA, and Spaan JA. Evidence that cell surface
charge reduction modifies capillary red cell velocity-flux relationships in hamster cremaster muscle. J Physiol 489: 193–201, 1995.
426. Vis MA, Bovendeerd PH, Sipkema P, and Westerhof N. Effect
of ventricular contraction, pressure, and wall stretch on vessels at
different locations in the wall. Am J Physiol Heart Circ Physiol
272: H2963–H2975, 1997.
427. Vis MA, Sipkema P, and Westerhof N. Modeling pressure-area
relations of coronary blood vessels embedded in cardiac muscle in
diastole and systole. Am J Physiol Heart Circ Physiol 268: H2531–
H2543, 1995.
428. Vis MA, Sipkema P, and Westerhof N. Compression of intramyocardial arterioles during cardiac contraction is attenuated by accompanying venules. Am J Physiol Heart Circ Physiol 273: H1003–
H1011, 1997.
429. Vis MA, Sipkema P, and Westerhof N. Modeling pressure-flow
relations in cardiac muscle in diastole and systole. Am J Physiol
Heart Circ Physiol 272: H1516 –H1526, 1997.
430. Vlahakes GJ, Verrier ED, Turley K, and Hoffman JI. Maximal
vascular conductance in right ventricular myocardial circulation.
Am J Physiol Heart Circ Physiol 266: H1363–H1372, 1994.
431. Vogel WM, Apstein CS, Briggs LL, Gaasch WH, and 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 51: 465– 478, 1982.
432. Wang L and Feng G. Nitric oxide and prostacyclin mediate coronary shear force-induced alterations in cardiac electrophysiology.
Med Hypotheses 63: 434 – 437, 2004.
1307
1308
WESTERHOF ET AL.
flow velocity patterns in thrombolysis in myocardial infarction flow
grade 2 in acute myocardial infarction: insight into mechanisms of
microvascular dysfunction. J Am Coll Cardiol 40: 1755–1760, 2002.
455. Yamamuro A, Akasaka T, Tamita K, Yamabe K, Katayama M,
Takagi T, and Morioka S. Coronary flow velocity pattern immediately after percutaneous coronary intervention as a predictor of
complications and in-hospital survival after acute myocardial infarction. Circulation 106: 3051–3056, 2002.
456. Yoshikawa J, Akasaka T, Yoshida K, and Takagi T. Systolic
coronary flow reversal and abnormal diastolic flow patterns in
patients with aortic stenosis: assessment with an intracoronary
Doppler catheter. J Am Soc Echocardiogr 6: 516 –524, 1993.
457. Yu Y, Tune JD, and Downey HF. Elevated right atrial pressure
does not reduce collateral blood flow to ischemic myocardium.
Am J Physiol Heart Circ Physiol 273: H2296 –H2303, 1997.
458. Zamir M. The Physics of Coronary Blood Flow. New York: AIP,
2005.
459. Zeng D, Ding Z, Friedman MH, and Ethier CR. Effects of
cardiac motion on right coronary artery hemodynamics. Ann
Biomed Eng 31: 420 – 429, 2003.
460. Zhao MJ, Zhang H, Robinson TF, Factor SM, Sonnenblick EH,
and Eng C. Profound structural alterations of the extracellular
collagen matrix in postischemic dysfunctional (“stunned”) but viable myocardium. J Am Coll Cardiol 10: 1322–1334, 1987.
461. Zinemanas D, Beyar R, and Sideman S. Effects of myocardial
contraction on coronary blood flow: an integrated model. Ann
Biomed Eng 22: 638 – 652, 1994.
462. Zinemanas D, Beyar R, and Sideman S. An integrated model of
LV muscle mechanics, coronary flow, and fluid and mass transport.
Am J Physiol Heart Circ Physiol 268: H633–H645, 1995.
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017
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