J Mol Cell Cardiol22, 375-390 (1990)

Lorex Award for Outstasdirrg Research

Interrelations between Coronary Artery Pressure, Myocardial

Metabolism and Coronary Blood Flow

Eric 0. Feigl*, Gregory W. Neat and Alice H. Huang

Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle,

WA 98195, USA
(Received May 1989, accepted in revisedform 7 .November 1989)

E. 0. FEIGL, G. W. NEAT AND A. H. HUANG. Interrelations between Coronary Artery Pressure, Myocardial
Metabolism and Coronary Blood Flow. Journal OI Molecular and Cellular Cardiology (1990) 22, 375-390.
Characteristically, the coronary circulation has been studied in the time-honored way of varying a single
experimental variable while attempting to hold other hemodynamic variables constant. This has produced two-
dimensional descriptions of coronary physiology where coronary blood flow vs. coronary artery perfusion
pressure, or coronary blood flow vs. myocardial oxygen consumption, are plotted. However, the physiology is
more complicated than these plots can show, because coronary blood flow and myocardial metabolism interact.
Accordingly, a three-dimensional analysis of coronary physiology has been made where coronary artery pressure
and myocardial oxygen consumption are the primary determinants of coronary blood Aow, but interactions
among all three variables are included. Data on coronary autoregulation and myocardial oxygen consumption
have been combined, while maintaining mass balance, to form a three-dimensional surface that describes local
metabolic control of coronary blood Bow. Using this description of state in three dimensions, simulations of
coronary physiology with and without coronary artery stenosis were performed which provide insight into the
simultaneous variations in coronary artery pressure, myocardial metabolism and coronary blood flow.

Introduction a nearly proportional change in coronary flow

The dominant factors that determine coron- and oxygen uptake is observed, with only
ary blood flow are coronary artery pressure small changes in the percentage of oxygen
and myocardial oxygen consumption. These extracted across the myocardium.
variables have been the subject of many physi- During normal conditions aortic pressure
ological studies in which coronary artery pres- and coronary artery pressure are equal. How-
sure or myocardial metabolic rate was the ever, the aortic pressure represents the after-
independent variable and coronary blood flow load for the left ventricle, and it has been
was the dependent response variable (Feigl, repeatedly observed that systolic pressure de-
1983). In a typical experiment in which velopment is a major correlate of left ven-
coronary artery pressure is experimentally tricular oxygen consumption (Braunwald,
varied, a relatively constant autoregulated 1971; Weber and Janicki, 1977; Suga, 1979;
coronary flow is observed in the middle range Bailer et al., 1981; Rooke and Feigl, 1982).
of pressures, while flow varies steeply with Therefore, it is not possible to study coronary
pressure above or below the autoregulatory pressure-flow relations with a constant my-
range. In an experiment on myocardial meta- ocardial metabolism simply by altering aortic
bolism, either cardiac pacing, augmented car- pressure. The usual solution to this problem is
diac afterload, infusion of catecholamines, or to hydraulically separate aortic and coronary
exercise might be used to increase myocardial pressures by cannulating the coronary artery
oxygen consumption. During these conditions and perfusing it with a pump. When the

*Dr. Eric Feigl has been awarded the Lorex Award for Outstanding Research.
Supported by NIHHL 16910.
0022-2828/90/040375 + 16 $03.00/O 0 1990 Academic Press Limited
376 E. 0. Feigl et al.

pressure-flow relation of the cannulated, in this analysis: first, as a tool to evaluate the
pump-perfused coronary circulation is effects of various assumptions on the shape of
studied, a family of autoregulation curves is the surface and, second, to calculate trajec-
observed, depending on the prevailing my- tories on the established three-dimensional
ocardial oxygen consumption; flow is auto- surface. To this end, programs were written in
regulated at a higher level with elevated my- FORTRAN and run on a CDC 6400 com-
ocardial metabolism than with a lesser metab- puter. The three-dimensional surface was gen-
olism (Mosher et al., 1964; Rouleau et al., erated using a FORTRAN subroutine
1979; Drake-Holland et al., 1984; Dole, 1987; “PICTURE” (Prueitt, 1973). A surface was
Vergroesen et al., 1987). generated from a matrix passed as a para-
Although coronary artery pressure and my- meter to PICTURE, where row and column
ocardial metabolism are often considered as numbers corresponded to pressure and oxygen
two independent variables that control coro- consumption values and the element value
nary blood flow, in fact these variables inter- was the flow for that particular row and
act through coronary flow, which is usually column. Given the matrix, generated from the
considered the response (dependent) variable. combination of physiological mass balance
If coronary blood flow is restricted, my- constraints and assumptions, PICTURE gen-
ocardial ischemia will ensue with a concomi- erated a surface that could be viewed from any
tant decline in contraction and metabolism. angle. Once the surface was established, traj-
Alterations in coronary flow in the normal ectories across it were calculated from the
range (without &hernia) also cause changes matrix and the familiar two-dimensional rel-
in myocardial metabolism. An augmentation ations involving two of the three primary
of normal coronary blood flow results in a variables. The determination of a trajectory
modest increase in myocardial metabolism. was done by either graphical techniques or use
This phenomenon is called the Gregg effect for of IMSL subroutines to analytically solve for
Donald Gregg, who first described this unex- the coordinates of the trajectory formed by the
pected observation (Gregg, 1958, 1963; Feigl, intersection of the surface with the two-
1983). The usual explanation for the Gregg dimensional relation.
effect is Lochner’s “garden hose” hypothesis,
whereby increased coronary perfusion stret-
ches myocardial fibers during diastole so that Normal values
cardiac contraction and metabolism are aug- A number of normal values for the dog have
mented by a Frank-Starling mechanism been taken from the literature and are given in
(Arnold et al., 1968; Feigl, 1983). Table 1. Round numbers in the normal range
The relationships between pressure, flow have been chosen in some cases for ease of
and metabolism are usually considered in the computation. The interpretations are not de-
time-honored way of two variables at a time, pendent on the specific values chosen, and any
i.e. the effects of pressure on flow, metabolism reasonable set of values will do, so long as they
on flow, and flow on metabolism or contrac- are internally consistent and maintain mass
tion. Recognizing that coronary pressure, flow balance. For example, the myocardial oxygen
and myocardial metabolism interact con- consumption and carbon dioxide production
tinuously, the purpose of this essay is to con- must be consistent with the arterial and ven-
sider these three variables simultaneously with ous blood gas contents. Critical assumptions
the aid of computer calculations and three- will be explicitly mentioned in the exposition.
dimensional graphs. In addition, the sigmoid
shape of the oxyhemoglobin dissociation curve
was included in the calculations, since this Exposition
parameter is difficult to hold in mind. The three primary variables-coronary artery
pressure, myocardial oxygen consumption
Methods and coronary blood flow-are plotted in three
dimensions as illustrated in Figure 1. Coro-
Computation nary blood flow is expressed as ml/min per
The computer provided two major functions gram of myocardium on the right side of the
 Coronary Physiology in Three Dimensions 377

graph. Since arterial oxygen content is const-

st 500 ant in this analysis (17.5 vol %), it is possible
$ t
to express coronary blood flow as oxygen
g 400- -2.4 ;
a delivery (flow x arterial 02 content), and this
E
is expressed as ~1 of 02 delivered/min per
gram of myocardium on the left side of Figure
1. Oxygen delivery is a helpful variable,
because the units are identical to those of
myocardial oxygen consumption (~1 of 02
consumed/min per gram of myocardium).
Also shown in Figure 1 is the plane of identity
where oxygen delivery and oxygen consump-
tion are exactly equal, meaning that oxygen
extraction equals lOOo/o. This may be visuali-
zed as a slanted plane of glass inside the three-
dimensional box delineated by the primary
variables. It is impossible for the myocardium
FIGURE 1. The three variables describing coronary to extract more oxygen than is delivered; thus
physiology are shown in a three-dimensional graph. The the 100% extraction plane is a lower bound-
combination of coronary artery pressure and myocardial
ary in the analysis. In other words, all real
oxygen consumption determine coronary blood flow.
Flow is given in two scales, ml (of bIood)/min per g of points lie above the lOOo/o extraction plane
myocardium and arterial oxygen delivery ~1 (of Oz)/min (coronary venous POT above zero), and there
per g of myocardium. Inside the box the slanted plane of can be no points below the lOOO;, plane,
100°/, oxygen extraction is shown. This plane represents because extraction would exceed 1OOO~~.
the condition when oxygen delivery and oxygen con-
sumption are equal. Because the heart cannot extract Having established the three-dimensional
more oxygen than is delivered, no points can lie below the axes and boundaries of the problem, it now
100°,\ extraction plane. remains to diagram a surface that describes

TABLE 1. Normal resting dog values assumed for calculations

Coronary Coronary
artery vein References

PO, (mm&) 100 19 Xhonneux and Shaper, 1969;

Feigl and D’Alecy, 1972; L&se ef
al., 1975; Heyndrickx ef al.,
1982; Dai and Bathe, 198%
Bathe et al., 1988
Pc-%o, (mm&) 36.8 49.3 Feigl and D’Alecy, 1972
PH 7.42 7.37 Feigl and D’Alecy, 1972
Hemoglobin (g/dl) 13.2 13.2
0, content (vol “/b) 17.5 4.3
Co, content (vol %) 46.4 57.6
Mean pressure (mmHg) 90 0

Myocardial values
Oxygen Metabolism [Mire,] (pl/min per g) 80 Messer et al. 1962;
Gregg et al., 1965;
Binak et al., 1967;
Restorff et al., 1977
Respiratory quotient [M~co,/Mtb,] 0.85 Katz and Feigl, 1987
0, extraction [A-V/A] ( yO) 75 Stone, 1980; Gwirtz and Stone,
1981
Temperature (“C) 37
Blood flow (ml/min per g) 0.6
378 E. 0. Feigl et al.

the coronary circulation inside the box of able literature on autoregulation, although
Figure 1 and above the plane of 100% extrac- true isomets without a Gregg effect probably
tion. This will be done with grid lines of have not been achieved (Mosher et al., 1964;
constant metabolism and lines of constant Drake-Holland et al., 1984; Dole and Nuno,
pressure. 1986; Vergroesen et al., 1987; Yonekura et al.,
1987). The steep portions of the isomets at the
right side of Figure 2 represent flow above the
hornets autoregulatory range. The inflection points in
The relationship between coronary pressure the isomets represent the transition from auto-
and flow is shown in Figure 2. The different regulation to non-autoregulated flow. The po-
lines in the graph represent the pressure-flow sition of the inflection points between 150 and
relation at different fixed levels of myocardial 170 mmHg coronary pressure is where the
oxygen consumption. These are the experi- coronary venous POT equals 25 mmHg, and
mental data that would be observed in an will be explained later. The steepening of the
autoregulation experiment if there were no different isomet slopes with increasing my-
Gregg effect, which will be explained later. ocardial oxygen consumption comes from ob-
The lines in Figure 2 are at exactly fixed servations on myocardial oxygen extraction,
values of myocardial metabolism and thus are as described in the next section on isobars.
isometabolism lines-called isomets hereafter.
The left portions of the isomets with shallow
slopes represent coronary autoregulation with Isobars
a constant myocardial oxygen consumption. Mohrman and Feigl (1978) perfused the
The first of the two major assumptions in this coronary circulation at 90 mmHg pressure
essay is encountered here; that isomets in the while varying left ventricular myocardial oxy-
autoregulatory range are linear straight lines. gen consumption and observed that the per-
This assumption is consistent with the avail- cent oxygen extraction varied in a linear man-
\
7

/ 4 2.0

1 I.l.ill..h
0 40 80
Coronary pressure (mmHg)

FIGURE 2. The relation between coronary pressure and coronary blodd flow is illustrated for different levels of
myorardial oxygen consumption. Each line is a line ofconstant oxygen metabolism called an “isomet”. Line segments to
the lrft of the klection points are in the autoregulatory range, segments to the right of this point are above the
.tutorrgulatory range.
 Coronary Ph)rsiology in Three Dimensions 379

ner as a function of oxygen consumption, as

shown in Figure 3. The different lines in
Figure 3 are at different fixed constant coro-
nary arterial pressures. The line at 90 mmHg
represents the experimental data of Mohrman
and Feigl (1978). The other lines represent
assumed values. This is the second major
assumption of the essay; the steepness (slope) of
the relation between oxygen extraction and
oxygen consumption (A oxygen extraction/A
oxygen consumption) is greater for low coro-
nary pressures (40 mmHg) than for high coro-
nary pressures (140 mmHg). It was found that
this second assumption was a necessary conse-
20 quence of the first major assumption (linear
isomets). If isomets are linear, then there
!
needed to be more oxygen extraction at low
coronary pressures, as has been observed ex-
0-I perimentally (Drake-Holland et al., 1984).
Myocardlal oxygen consumption (!Al/mln per g) This second assumption may be restated as:
The slopes of the autoregulatory portions of
FIGURE 3. The percent oxygen extraction (A-V/A)
isomet lines become steeper with increasing
across the myocardium as a function of myocardial oxy-
gen consumption is shown for three constant coronary
myocardial metabolism (see Discussionj .
artery pressures. The data for the coronary pressure of 90 If the relationship between myocardial oxy-
mmHg are taken from Mohrman and Feigl (1978). gen metabolism and the percent oxygen ex-
traction across the myocardium is known,
then the relation between coronary blood flow
and myocardial oxygen consumption may be
calculated if the arterial oxygen content is
specified (17.5 ~01%). The result of such a
calculation for the data at a constant coronary
artery pressure of 90 mmHg is illustrated in
Figure 4. Note that Figure 4 is the equivalent
of looking into the three-dimensional box of
Figure 1 from the right side. Also note that
radial lines in this figure represent lines of
constant oxygen extraction. The curved line
representing coronary blood flow as a function
of myocardial oxygen consumption at a const-
ant coronary pressure will be called an isobar.

Three-dimensional surface
The combination of equally spaced isomets
and isobars produces a three-dimensional grid
that illustrates a surface in the primary vari-
Myocordlal oxygen consumption
( pl/min per gl ables of pressure, metabolism and flow, as
shown in Figure 5. This surface represents the
FIGURE 4. The straight line increase in extraction
coronary flow that will result with any com-
with myocardial oxygen consumption shown in Figure 3
equals a curved line when plotted as coronary flow vs.
bination of myocardial oxygen consumption
myocardial oxygen consumption. A line describing flow and coronary artery blood pressure. For
and metabolism with a constant coronary artery pressure example, the dot in Figure 5 represents the
is called in isobar. normal resting point for the dog given in
 380 E. 0. Feigl et af.

FIGURE 5. The gridded three-dimensional surface describing metabolic control ofthe coronary circulation is shown.
The surface lies above the plane of 100% extraction and has two main regions: (1) a zone of autoregulation which is
relatively flat between the intersection with the lOO’/b extraction plane on the left and a crease in the gridded surface on
the right; and (2) a region where coronary pressure is above the autoregulatory range to the right of the crease. Grid
lines running from left to right are isomets, grid lines running from front to back are isobars. The dot indicates the
normal point with a coronary pressure of 90 mmHg, an oxygen metabolism of 80 pl/min per g, and a coronary flow of
0.6 ml/min per g. Coronary venous oxygen tension values have been added to the three-dimensional surface. On the left
margin, the surface intersects the lOOq/, extraction plane where venous oxygen tension equals zero. The upper boundary
of coronary autoregulation occurs at a coronary venous oxygen tension of 25 mmHg, which is the crease in the gridded
surface.

Table 1, where myocardial oxygen metabol- Reported values for myocardial oxygen con-
ism is 80 pl/min per g, coronary pressure is 90 sumption while the heart is artificially per-
mmHg, and coronary flow is 0.6 ml/min per g. fused during potassium arrest range from 14 to
The margins of the gridded coronary sur- 20 &min per g (McKeever et al., 1958; Boerth
face deserve special attention. The left margin et al., 1969; Suga et al., 1983). A value of 20
of the surface ends where the downward slop- @/min per g was chosen for visual clarity. A
ing surface intersects the plane of lOOo/o oxy- small “tongue” of the coronary surface ex-
gen extraction. The line at the left edge of the tends down to the origin (0, 0, 0) of the three-
gridded surface is thus a series of points where dimensional graph. This tongue represents an
oxygen extraction would be 100% with a area of ischemia where myocardial oxygen
coronary venous oxygen tension of zero. At consumption is pathologically low (below 20
the front margin of the surface there is an @/min per g) and the coronary venous oxygen
abrupt edge at Mi’o, =20 pl/min per g. This tension is in the range between 0 and 10
represents the lower bound of myocardial oxy- mmHg.
gen consumption as observed in potassium- The crease running from front to back on
arrested, perfused hearts. Presumably potas- the right side of the surface represents the
sium arrest with adequate coronary perfusion transition from autoregulation to pressure-
represents the lower limit ofmyocardial metab- dependent flow above the autoregulatory
olism in the absence of ischemia. The abrupt range. This crease is a line of constant coro-
discontinuity with a blank vertical face ex- nary venous oxygen tension equal to 25
tending down to the 100% extraction plane mmHg. Dole and Nuno (1986) demonstrated
(cf. Fig. 1) represents the end of real points, that coronary autoregulation is dependent on
since it is assumed that myocardial oxygen coronary venous oxygen tension, with strong
consumption does not fall below 20 pl/min per autoregulation when coronary venous oxygen
g, except if the myocardium is made ischemic. tension was below approximately 25 mmHg
 Coronary Physiology in Three Dimensions 381

and a complete loss of autoregulation when

oxygen tension exceeded 32 mmHg. A discrete
venous Paz value of 25 mmHg was chosen
here and is illustrated as a sharp discontinuity O2 extractlon 93.9%- ~~ -:
for visual clarity. The steep portions of isomets
above the autoregulatory range to the right of
the crease are not based on data and are
arbitrarily drawn, because little information is
available on flow and pressure at constant
metabolism in this region.

Venous oxygen tension

i-,--
If the hemoglobin and arterial oxygen cont- 8 IO
ents are constant, then a given value of my- Venous PO* CmmHg)
ocardial oxygen consumption and coronary
flow determines a specific venous oxygen ten- FIGURE 6. The hypothetical ischemic degradation of
sion. The venous oxygen tensions correspond- myocardial metabolism is illustrated. It is assumed that
venous oxygen tension reflects myocardial tissue oxygen
ing to the three-dimensional surface are ill- tension and that &hernia is present when venous oxygen
ustrated in Figure 5. These values were deter- tension falls below a threshold value of 10 mmHg. The
mined using the Olszowka and Farhi ( 1968) hypothesis is that below 10 mmHg the prevailing my-
subroutines for calculating hemoglobin blood ocardial oxygen consumption falls linearly to zero as a
gas values. As mentioned before, the left hand function of the oxygen tension.
edge of the gridded surface is the line of venous
Paz equal to zero and the crease in the surface is unlikely to be exactly correct, but any
is the line where venous Pal equals 25 mmHg. monotonic relation between venous oxygen
The very uneven spacing between oxygen tension and myocardial oxygen consumption
tension lines is due to the sigmoid shape of the will yield a similar interpretation.
oxyhemoglobin dissociation curve. Because Gregg’s phenomenon is the observation
tissue oxygen tension is heterogeneous and that a change in coronary blood flow results in
difficult to measure, the venous oxygen tension a change in myocardial oxygen consumption
is used as a reflection of the average tissue in the absence of ischemia. Downey ( 1976)
oxygen tension. Furthermore, venous oxygen provides a nice quantitative description of the
tension may be rigorously calculated by mass Gregg effect in that left ventricular myocardial
balance. contractile force increased 15% from the auto-
perfusion point with a doubling of coronary
blood flow. The simplifying assumption made
Effect ofjfow on metabolism here is that the increase in myocardial oxygen
Severe restriction of coronary flow produces consumption equals the increase in contractile
ischemia which results in a decline in my- force. Yonekura et al. (1987) found a larger
ocardial function and a concomitant dimi- correction for the Gregg effect in the right
nution of myocardial oxygen consumption. than the left ventricle. Based on Downey’s
The literature indicates that a restriction of data, the relation between coronary blood
coronary blood flow results in myocardial flow and left ventricular oxygen consumption
ischemia when coronary venous oxygen ten- during nonischemic conditions is illustrated in
sion falls to about 10 mmHg (Nakamura et al., Figure 7.
1969; O’Riordan et al., 1977), so a critical The Gregg phenomenon (Fig. 7) and effects
level of 10 mmHg was chosen. Furthermore, it of ischemia (Fig. 6)) including the hemoglobin
was arbitrarily assumed that during progress- calculation (allowing the transformation from
ive ischemia the prevailing oxygen consump- venous POT to coronary flow), are combined
tion would decrease as a linear function of the in Figure 7. This figure illustrates the overall
venous oxygen tension below 10 mmHg, as effect of coronary blood flow on myocardial
illustrated in Figure 6. This linear assumption oxygen consumption. Above a venous oxygen
382 E. 0. Feigl et al.

z
5 60
FL 7 mmHg, 95.9%
E
3
F 6 mmHg. 96 5%

i j&jg!; , , , , , , , ,
0.6 0.8 1.0 1.2 I

Coronary flow (mllmln per gi

FIGURE 7. The combined Gregg and ischemic effects on myocardial oxygen consumption when coronary blood flow
is independently varied from an initial normal point with an oxygen consumption of 80 pl/min per g. The values of
venous PO* and percent oxygen extraction are given at various points. The slope of the Gregg effect is from Downey
(1976).

FIGURE 8. A simulation of an autoregulation experiment is illustrated where coronary pressure is independently

varied above and below the initial normal point at the dot (coronary pressure 90 mmHg and myocardial oxygen
consumption 80 pl/min per g). Increasing coronary pressure above the normal point results in a modest increase in
coronary blood flow because of autoregulation and a slight increase in oxygen consumption secondary to the increase in
flow by the Gregg effect. When coronary venous oxygen tension exceeds 25 mmHg (crease in the surface),
autoregulation is lost and flow increases steeply with increasing coronary pressure. Decreasing pressure below the
normal point results in a modest decrease in flow and oxygen consumption until the critical venous oxygen tension of 10
mmHg is reached. Below this threshold ischemia ensues and myocardial oxygen consumption falls steeply with a
concomitant decline in coronary flow. Cardiac rate, preload and afterload are assumed constant.
 Coronary Physiology in Three Dimensions 383

F
-
240 -

Coronary pressure (mmHg)

FIGURE 9. The three-dimensional trajectory of simulated autoregulation shown in Figure 8 is replotted here in the
usual two dimensions of pressure and flow. Autoregulation of flow is observed in the middle range of pressures with flow
being steeply pressure dependent below and above the autoregulatory range. Concomitant changes in oxygen
consumption and venous oxygen tension from the three-dimensional analysis are given. The dashed isomet line
renresents the pressure-flow relation that would occur ifthere were no changes in oxygen consumption due to the Gregg
effect or ischeiia.

tension of 10 mmHg, the Gregg effect is seen, that results at coronary pressures below 40
whereas below a venous oxygen tension of 10 mmHg.
mmHg, the effects of ischemia are observed. A two-dimensional representation of the
Once again, a sharp discontinuity between same trajectory is given in Figure 9. The solid
regions was assumed for the sake of clarity. line in Figure 9 is the two-dimensional shadow
that would be cast on the back wall of the box
in Figure 8 by a copper wire laid along the
Simulation of autoregulation three-dimensional surface trajectory in Figure
The interrelations between coronary artery 8. Also shown in Figure 9 are the values of
pressure, myocardial oxygen consumption, myocardial oxygen consumption and the ven-
and coronary blood flow are now assembled so ous oxygen tensions determined from the
that simulated experiments may be perfor- three-dimensional surface. The simulated
med. If cardiac preIoad, afterload and heart autoregulation experiment indicates that the
rate are assumed constant, then the effects of lower limit of autoregulation is at a mean
an experiment in which coronary artery pres- coronary pressure of approximately 40 mmHg
sure is varied may be calculated, incorporat- where myocardial ischemia also begins, and is
ing the relationships expressed in Figure 7, as in good agreement with the results of Canty
illustrated in Figure 8. Coronary artery pres- (1988).
sure was varied above and below the initial
normal point (Table 1) shown by the dot in
Figure 8. The line in the figure is a trajectory Simulation oj increased metabolism
on the three-dimensional surface. It may be The arrow in Figure 10 illustrates the three-
observed that myocardial metabolism de- dimensional trajectory of myocardial oxygen
creases modestly as coronary pressure is re- consumption, coronary pressure and coronary
duced in the autoregulatory range due to the blood flow when metabolism is increased from
Gregg effect. However, there is a bend in the the normal point (dot) with a constant coro-
trajectory below which myocardial metabol- nary artery pressure of 90 mmHg. It may be
ism and coronary blood flow fall steeply. In observed that the coronary venous oxygen
this simulation the loss of autoregulation is tension declines modestly as metabolism is
due to the ischemia (Po2 less than 10 mmHg) augmented. The trajectory of the arrow repre-
384 E. 0. Feigl et al.

FIGURE 10. A simulation where myocardial oxygen consumption is independently varied while coronary artery
pressure is held constant at 90 mmHg. Oxygen consumption is increased from the normal value of80 pl/min per g (dot)
along the 90 mmHg coronary pressure isobar (arrow) It may be observed that coronary venous oxygen tension (dashed
lines) falls slightly as oxygen consumption and coronary flow increase. The two-dimensional representation of this
increase in coronary flow as oxygen consumption is augmented is given in Figure 4.

senting augmented metabolism with a con- nonlinear hydraulic resistor in series with the
stant coronary artery pressure of 90 mmHg is normal downstream coronary vascular resis-
the two-dimensional isobar illustrated in Fig- tance. The pressure drop (AP) across a steno-
ure 4. Inspection of Figure 10 reveals that if sis may be calculated from empirical equa-
there were a modest increase in coronary tions (Gould, 1978, 1985; Lipscomb and
pressure accompanying the increase in metab- Hooten, 1978; Brown et al., 1984) and the
olism, a constant venous oxygen tension would result of such a calculation is illustrated in
be observed. Aortic (coronary) pressure often Figure 11. This figure indicates the pressure-
increases in situations such as exercise and flow relation of a simulated stenosis of a cir-
excitement, when myocardial metabolism is cumflex or left anterior descending coronary
augmented. Thus, the relatively constant artery of a dog that perfuses 50 g of left
coronary sinus oxygen tension observed dur- ventricular myocardium. It may be seen that
ing these conditions may be due, in part, to the drop in pressure across the stenosis is
the increased coronary pressure interacting modest (18 mmHg) at a normal resting coro-
with metabolism and flow, as described by the nary flow of 0.6 ml/min per g. However, if
surface. greater flows are required by the myocardium
the pressure gradient rises steeply in a non-
linear manner, and essentially all of the aortic
pressure available at the stenosis inIet may be
Stenosis characteristics lost in the stenosis at high flows. During rest-
Atherosclerosis may result in a stenosis of a ing conditions the pressure drop across the
coronary artery so there is a drop in pressure stenosis does not decrease coronary pressure
between the aorta and the coronary artery below the autoregulatory range, and the auto-
distal to the stenosis. A stenosis represents a regulatory mechanism in the coronary micro-
 Coronary Physiology in Three Dimensions 385

100, coronary atherosclerosisare normal function

23 : 3 m m 0.6 mm=d,,, at rest but ischemic chest pain (angina pec-
80\ Li ‘p,I- toris) during exertion when myocardial metab-
ZLYc - 80% stenosis
6% Perfused weight=50 g olism is augmented. This condition may be
54 6Ok simulated with the information previously de-
veloped incorporating the hemodynamic
characteristics of a stenosis.In Figure 12, the
stenosisdescribed in Figure 11 is added to the
three-dimensional coronary control surface.
The dimensions are unchanged, except that
c i- 1 .I 11-l 1 .l 1 I .i ILL I 1

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 coronary pressure now denotes the coronary
Coronary flow (ml/mln per g) artery pressure distal to a stenosis with a
constant aortic pressure of 90 mmHg. The
FIGURE 11. The nonlinear hydraulic resistor charac-
normal control point without a stenosis is
teristics of a coronary artery stenosis arc illustrated. The
pressure drop (AI’) across the stenosis is a very nonlinear shown as a dot; the simulation is shown as an
function of the flow through the stenosis. This has the upward arrow trajectory on the surface. The
effect of greatly decreasing coronary artery pressure distal simulation begins with a resting myocardial
to the stenosis at high flows. This stenosis is used in the oxygen consumption of 80 pl/min per g, but
simulation shown in Figure 12. From Brown et al. (1984).
the coronary artery pressure distal to the
circulation maintains a nearly constant flow, stenosisis 18 mmHg lower than the aortic
asdescribed earlier. pressurebecauseof the stenosis.
A primary increase in myocardial metabol-
ism is simulated with a constant aortic pres-
Simulation of coronary stenosis sure of 90 mmHg, similar to the simulation in
The characteristic symptoms of a patient with Figure 10, except in the present case any

FIGURE 12. A simulation where myocardial oxygen consumption is independently varied in the presence of a
coronary artery stenosis while aortic pressure is constant at 90 mmHg. The simulation begins at a normal oxygen
consumption of 80 pl/min per g, but the coronary artery pressure distal to the stenosis is 18 mmHg below the aortic
pressure. As myocardial oxygen consumption is increased, metabolic vasodilation distal to the stenosis increases flow.
However, there is a concomitant fall in coronary artery pressure and venous oxygen tension because of the stenosis. This
path continues upward until the threshold for ischemia is reached at a venous oxygen tension of 10 mmHg. Beyond this
point, ischemic dysfunction ensues.
386 E. 0. Feigl et al.

increase in flow results in a pressure drop first rule assumed was that an isomet is a linear
across the stenosis and thus a decline in coron- straight line. This was based on inspection of
ary artery pressure. This decrease in pressure pressure-flow data in autoregulation experi-
may be observed as the leftward movement of ments (Mosher e! al., 1964; Drake-Holland et
the trajectory as metabolism is progressively al., 1984; Dole and Nuno, 1986; Dole, 1987;
augmented. The increased metabolism results Vergroesen et al., 1987). These data indicate
in an augmented flow, but at the cost of a rather straight line relations between pressure
declining coronary pressure and more oxygen and flow in the autoregulatory range. Since
extraction. This trajectory toward a high the Gregg effect contributes only a small
metabolism and low coronary pressure distal change during autoregulation, it is probably
to the stenosis continues until the critical level reasonable to assume that isomets in the auto-
of 10 mmHg venous (myocardial) oxygen regulatory range are linear. The linear extra-
tension is reached. Beyond this point, ischemia polation of isomets into the ischemic range in
results, with myocardial dysfunction. the present study is pure assumption and
In summary, the trajectory shown in Figure makes calculations in the areas of ischemia
12 is a simulation of what occurs when my- (coronary venous POT below 10 mmHg) inse-
ocardial metabolism is increased in the pres- cure. However, to assume an arbitrary non-
ence of a coronary artery’stenosis.The initial linear extrapolation seemed unwarranted.
normal metabolism is maintained at a lower The linear increase in myocardial oxygen
than normal coronary pressure distal to the extraction with increasing myocardial oxygen
stenosis by microcirculatory autoregulation consumption at a constant coronary artery
and a moderate decrease in coronary venous pressure of 90 mmHg was taken from Mohr-
oxygen tension. As metabolism is augmented man and Feigl ( 1978). For a fixed arterial
there is an inadequate flow increase and both oxygen content this relation yields by simple
coronary pressure and coronary venous oxy- mass balance, the gently curved isobar shown
gen tension fall because of the stenosis. A in Figure 4. If a constant oxygen extraction
critical level of myocardial oxygen tension is were assumed, an isobar would be a radial line
reached and further, myocardial stimulation of constant extraction in Figure 4.
results in ischemia, with a decrease in myo- The second major assumption was that my-
cardial function. ocardial oxygen extraction increases faster
with myocardial oxygen consumption at low
than at high coronary artery pressures, as
shown in Figure 3. This assumption is equiva-
Discussion lent to the slopes (Aflow/Apressure) of the
These simulation results indicate that an in- autoregulatory portions of isomet lines becom-
ternally consistent description of left ventri- ing steeper with increasing myocardial meta-
cular coronary physiology may be made from bolism, as illustrated in Figure 2. The litera-
presently available data. The three- ture is divided on this point. Mosher et al.
dimensional surface shown in the figures may (1964) show a figure with steeper autoregu-
be thought of as a description of state for local lation slopes at high, compared with low,
metabolic control of coronary blood flow. This myocardial oxygen consumption. Drake-
three-dimensional surface resembles the works Holland et al. (1984) observed a steepening
of Allela et al. (1955), Drake-Holland et al. and then a flattening of autoregulatory slopes
( 1984)) and Vergroesen et al. ( 1987) that were with augmented myocardial oxygen con-
presented in two dimensions, and is an exten- sumption. Dole and Nuno (1986) observed
sion of the concepts of these workers. little change in the slope of isomet lines when
an estimated Gregg effect was subtracted. Ver-
groesen et al. (1987) did not detect a signifi-
cant change in the autoregulatory slope with
Assumptions increases in metabolism, but their Figure 7
In the absence of a complete set of gridded shows a modest steepening of the autoregu-
data it is logical to choose simple rules for latory slope with increasing oxygen
generating a three-dimensional surface. The consumption.
 Coronary Physiology in Three Dimensions 387

Simplijications Constant substrate

The following simplifications have been made. The calculations are based on a constant
respiratory quotient (CO,/O,) of 0.85 with-
out changes in metabolic substrate. This is
Absence of neural ezects probably reasonable during autoregulation,
The description does not include the action of but less so during ischemia.
adrenergic a- and /?-receptor-mediated coro-
nary vascular effects. Only local metabolic
coronary control has been incorporated. a- Absence ojcollateral vessels
Receptor-mediated coronary vasoconstriction The effects of collateral vessels are not in-
competing with local metabolic control cluded in the calculations. This is another
(Mohrman and Feigl, 1978) would lower the factor that makes the simulations during
three-dimensional surface. In other words, the ischemic conditions less reliable than during
addition ofa-receptor vasoconstriction to local normal perfusion.
metabolic control would result in a diminished
flow and coronary sinus oxygen tension for
any given combination of coronary pressure Absence of a pressure at zerojow (PZF)
and oxygen consumption.
During prolonged diastoles coronary blood
flow ceases while coronary pressure is still
above zero (Bellamy, 1978). The mechanisms
Absence of phasic effects
responsible for the PZF phenomenon are com-
Both arterial pressure and coronary blood plicated and incompletely understood, but
flow are quite phasic, with most of coronary involve coronary vascular capacitance and the
artery inflow occurring during diastole. Mean action of an intramyocardial pump (Klocke et
pressures and flows have been used in all al., 1985; Spaan, 1985). It is unclear to what
calculations. Since phasic systolic interruption extent these factors need to be included in the
of coronary flow has little effect on mean flow steady-state analysis made in the present
(Katz and Feigl, 1988), this is probably not an study. For practical purposes the coronary
important limitation. artery pressures plotted in the figures may be
thought of as the effective pressure above PZF.
In other words, PZF has been assumed to be
Sharp transitions zero, and if a PZF needs to be added to the
For ease in computation and visual clarity the analysis this would only represent a trans-
transitions between various states of the coro- lation of the pressure axis.
nary circulation (autoregulation, ischemia,
etc.) are illustrated as sharp discontinuities.
.Normal and ischemic conditions
The foregoing indicates that the three-
Homogeneous left ventricle dimensional description of coronary physi-
The calculations do not include transmural ology based on experimental data is reason-
differences in the left ventricular wall. It is well ably sound in the normal autoregulatory
recognized that compressive forces are greater range, but speculative in the ischemic zone.
in the inner layers than in the outer layers of This means that the portions of the simul-
the left ventricle, and that the inner layer is ations that lie above the 10 mmHg oxygen
more vulnerable to ischemia (Schaper, 1979; tension ischemic threshold are probably valid.
Hoffman, 1987). The assumption of trans- Thus the description of the Gregg effect (Figs 8
mural homogeneity is probably reasonable for and 9) during a simulation of autoregulation
describing pressure-metabolism-flow rel- seems realistic. An interesting outcome of
ationships during normal conditions but may these calculations is that the lower limit of
not be valid during ischemia, since autoregul- autoregulation occurs at about the threshold
ation is lost earlier in the inner than the outer for ischemia, and that the sharp decline in
layer of the left ventricle (Guyton et al., 1977). flow with pressure below this point may be
388 E. 0. Feigl et al.

TABLE 2. Fraction of the dog heart supplied by the circumflex and left anterior descending arteries

Body Total heart LAD LCX

n weight (kg) weight (g) weight (g) weight (g) Ratio

45 28.3 f 2.6 185.3 f 29.3 71.8 + 12.2 0.390 f 0.050

13 27.2 f 1.7 190.3 f 19.7 55.8 + 9.5 0.293 + 0.042

Values are mean + S.D. LAD, area perfused by left anterior descending artery; LCX, area perfused by left circumflex
artery; Ratio, the fraction of the total heart supplied by the LAD or LCX.

ascribed to ischemia (Figs 8 and 9). Ischemia gen consumption expressed per mass of per-
is a plausible explanation for the loss of auto- fused myocardium and without venous oxy-
regulation that is consistent with the experi- gen values it is not possible to compare quant-
mental data of Canty (1988). itative results between different experiments
Similarly, the simulation of increasing my- and laboratories.
ocardial metabolism in the presence of a
coronary artery stenosis (Fig. 12) seems real-
istic above the ischemic threshold. That is, the
fall in coronary artery pressure distal to the Conclusion
stenosis and the decline in coronary venous Data on coronary pressure, myocardial meta-
oxygen tension appear to be reasonable in the bolism and coronary blood flow from a num-
autoregulatory range. ber of sources have been brought together into
an internally consistent three-dimensional de-
scription of local metabolic regulation of
A plea coronary blood flow. In addition, simulta-
Despite the many experiments on coronary neous computations of blood hemoglobin sat-
physiology that have been published, only a uration have been made, which permit a
few were found with data that could be ap- calculation of the corresponding venous oxy-
plied to the calculations made here. A fre- gen tensions. This three-dimensional descrip-
quent problem is that coronary blood flow is tion of state permits simulations of autoregul-
expressed as ml/min rather than ml/min per g ation and increases in myocardial metabolism,
of perfused left ventricular myocardium. If it with and without coronary stenosis. The re-
is not possible to demarcate the perfused sults emphasize that, because coronary venous
region with an intra-arterial injection of dye, oxygen tension is normally below 20 mmHg,
the perfused weight may be estimated from there is little leeway for increased oxygen
the values given in Table 2. An additional extraction across the myocardium and the
problem is the lack of coronary venous blood heart is always close to ischemia. The three-
values for oxygen tension. This is a plea to dimensional analysis provides an appreciation
authors and editors to report arterial and of the simultaneous interaction between
venous values of oxygen tension and oxygen coronary artery pressure and myocardial
content in addition to myocardial oxygen con- metabolism, which are the major deteminants
sumption. Without flow and myocardial oxy- of coronary blood flow.

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