Hemodynamic Principles in the Control

of Coronary Blood Flow

STEPHEN E. EPSTEIN, MD, RICHARD 0. CANNON III, MD,

and THOMAS L. TALBOT, MME

The effects of atherosclerotic epicardial stenoses arteries. Studies have also shown the clinical im-
on coronary vascular resistance can be understood portance and influence of dynamic alterations in
in terms of basic principles of fluid mechanics. Re- coronary resistance, occurring either at the large or
sistance is directly related to the pressure drop small vessel level. In addition, compressive forces
across the stenosis and inversely related to flow. exerted by the myocardium or by elevated intra-
Even with a fixed anatomic stenosis, however, re- ventricular pressures can increase coronary vas-
sistance is not fixed; it increases as flow across the cular resistance, and thus interfere with myocardial
stenosis increases. This exacerbates the pressure perfusion. All of these factors must be considered
drop across the stenosis that develops as a result in order to obtain a comprehensive understanding
of flow; at high flows, large pressure drops can of the mechanisms leading to myocardial ischemia
occur. This characteristic of flow through stenotic and, therefore, to the clinical syndrome of angina
lesions can contribute to a “steal” phenomenon pectoris.
between either epicardial or intramural coronary (Am J Cardiol 1985;58:4E-10E)

The normal coronary system can be thought of, in driving pressure on myocardial flow can be defined by
simplified terms, as consisting of large epicardial vessels the equation*:
that normally offer little intrinsic resistance to myo-
cardial flow (RI in Figure 1) and intramyocardial arter- Q=Ap/R,,
ies and arterioles (Rs in Figure 1) that, because of their where Q is blood flow, AP is the driving pressure across
small diameter, are the major source of coronary vas- the coronary bed and RZ is the coronary arteriolar
cular resistance. Because of their well-developed media, resistance.
they have the capacity to alter profoundly the resistance
to coronary blood flow. RI and Rs are in series, and Coronary Flow Reserve
hence the total resistance of the coronary circuit is ex- The arterioles dynamically alter their intrinsic tone
pressed as the algebraic sum of RI and Rs. Because the in response to the demands of the myocardium for
resistance to myocardial flow offered by the arterioles oxygen. As a result of this autoregulatory system,
(Rs) is substantially greater than that of the epicardial myocardial oxygen delivery and myocardial oxygen
vessels (RI), Rr vessels can be largely ignored. Thus,
myocardial blood flow is inversely related to arteriolar l Use of this and most subsequent equations assumes steady, fully
resistance and directly related to the coronary driving developed laminar flow through a rigid tubular system, conducting a
pressure. The influence of arteriolar resistance and fluid of constant density and viscosity. Further, lesions are treated as
axially symmetric reductions in luminal diameter and the associated
end effects are neglected. Although calculations based on these sim-
From the Cardiology Branch, National Heart, Lung, and Blood Institute, plifications are obviously subject to error when applied to a system as
National Institutes of Health, Bethesda, Maryland. complex as the circulatory system, the simplifications are used only
Address for reprints: Stephen E. Epstein, MD, Chief, Cardiology to derive concepts of the general magnitude of the changes in flow that
Branch, National Heart, Lung, and Blood Institute, National Institutes occur with narrowing of the cross-sectional area, and therefore resis-
of Health, Bethesda, Maryland 20205. tance, of a given coronary vessel.’

4E
demand are tightly couplied; when myocardial oxygen epicted in Figure 3. It has been determined
mands increase, the resistance vessels dilate and that complex interactions within the stenosis and
reby permit myocardial flow to increase in propor- poststenotic vessel lumen occur as flow changes, thereby
tion to the increased oxygen demands. obviating the linear model and introducing second- and

As an atherosclerotic lesion causes luminal narrowing

of a large epicardial artery, this originally low resistance
vessel is transformed into one that now offers sub-
JO‘”
stantial resistance to flow. Because autoregulatory in-
fluences alter arteriolar resistance in such a way as to
maintain the appropriate relation between myocardial
flow and myocardial oxygen demands, an increase in RI
can be offset, to a point, by a decrease in Rs. However,
the resistance of the large vessel lesion becomes flow-
limiting once the ceiling of the vasodilator reserve ca-
pacity of the arterioles is reached. Once vasodilator re-
serve has been exhausted, flow can no longer increase
(unless the driving pressure across the coronary bed
increases). Hence, the capacity for flow to increase
during exercise is compromised, and myocardial
ischemia results when the critical level of myocardial
oxygen demand that cannot be met by increases in
oxygen delivery is exceeded. Resting flow decreases and
% STENOSIS
angina at rest occurs when further increases in Rr
occur. FIGURE 2. Influence of degree of stenosis on autoregulatory mecha-
nisms that maintain appropriate levels of myocardial oxygen delivery.
This series of events is depicted diagrammatically in As epicardial coronary resistance (RI) increases because of increased
Figure 2. The curves were derived using the linear stenosis severity, arteriolar resistance (Rs) decreases, thereby main-
equation: taining total resistance (and thus flow) at normal levels. Once vasodilator
reserve of RP is exhausted, however, further increases in RI lead to
decreases in flow. (See text for details.)

with the assumption that as RI (epicardial resistance)

increases, Rs (arteriolar resistance) decreases to main-
tain constant flow. The shape and inflection point of the
flow curve, using this linear model of flow, differ from
-I y = 3.7- i O(lO-2lx +Z.4(lO-4lx2 -6.O(,O‘6)x3

the shape and inflection point of experimentally derived

SO DEV= 0.021
- 0 io 4b 6.0 80 I0 0

PER CENT LESION BY DIAMETER Ix)

FIGURE 3. Influence of percentage of diameter narrowing of an epi-

cardial coronary artery on coronary flow under baseline conditions
(dashed line), and in response to a vasodilator stimulus (solid line). The
appropriate coronary flow response is limited by less severe stenoses
during vasodilator stimulus than those that interfere with baseline flow.
FIGURE 1. Diagrammatic representation of a coronary artery. Rr sig- Flows are expressed as multiples of control resting mean values before
nifies resistance to flow caused by large conductance vessels and Rs application of vasodilator stimulus. The shaded area represents the
represents resistance to flow caused by small resistance vessels or range of values measured in individual dogs. r = correlation coefficient,
arterioles. P = driving pressure across the coronary bed. Reprinted with DEV = mean square of deviations. Reprinted with permission from Am
permission from Am J Cardioi.r7 J CardioLg
 third-order effects, as demonstrated by the shape of the
curves in Figure 3, and the third-order polynomial
equations that best fit the curves.
Ischemia occurs under baseline conditions only when
there is relatively severe stenosis of the epicardial vessel;
as depicted in Figure 3, baseline flow (dashed line) does
not decrease until there is 80 to 85% narrowing of the
vessel diameter (assuming a normal epicardial vessel to
be between 3 and 4 mm). However, the large flows re-
quired following potent vasodilator stimuli (such as
exercise or the infusion of vasodilator agents) will not
be attainable when much less severe epicardial coronary
stenoses are present. For example, in the presence of a
,diameter narrowing of 50 to 60%, baseline flow is
maintained as a result of the arterioles dilating to pre-
serve normal levels of total coronary resistance. This
utilizes part of the vasodilator reserve; hence, the ap-
propriate coronary flow response to an exercise load that
requires an increase in coronary flow of 3- to 4-fold
cannot be attained (solid line, Fig. 3). With more intense
exercise, even less severe stenoses will result in an in-
adequate flow response.
The flow responses to exercise and the development
of exercise-induced angina are shown in Figure 4. As
exercise intensity increases, the arterioles dilate and
resistance to flow decreases; myocardial blood flow in-
creases appropriately so that there is no flow deficit or
ischemia. When an epicardial vessel is significantly
narrowed, the arterioles dilate to maintain baseline
coronary resistance at normal levels; they have, there-
fore, impinged on their vasodilator reserve, and even low
levels of exercise exhaust the remaining reserve. Further
increments in exercise intensity can no longer be ac-
companied by further decreases in coronary resistance,
and no further increments in flow can occur. This results
in a flow deficit, causing myocardial ischemia.
Influence of Stenoses on Coronary Resistance
The magnitude of the effects of different degrees of
coronary stenosis on coronary resistance can be appre-
ciated by considering some simplified hydrodynamic
principles. For example, Poiseuille’s law states:
where Q is flow, r is the radius of the vessel, p is the
viscosity of blood, AP is the driving pressure across the
coronary bed and L is the length of the vessel or ob-
structing lesion. Because
R = AP/Q,
then
R _ 8P.L _ g(O.04) x 16 x L = 1.63 X L
7rr4 xD4 D4 ’
where R is resistance to flow and D is the diameter of the
vessel. Thus, resistance to flow is directly proportional
to the length of the lesion or vessel but, most impor-
tantly, is inversely proportional to the fourth power of
the vessel diameter.
This is best illustrated by the graphic representation
of this equation (Fig. 5), which ignores the potential
impact that compensatory changes in Rs would exert
on total coronary resistance. In the normal situation, the
epicardial coronary artery, with a diameter averaging
about 3 mm, offers little resistance to blood flow; the

Flow Deficit
* lschemia
Length
of Lesion

30

RES
20
(mm-Hg/mL/sec)

Rest 4 Exercise -
and
4 Myocardial O2
Demands
0
FIGURE 4. Diagrammatic representation of the relation between 0 1 2 3 4 5
myocardial oxygen demand and myocardial oxygen supply. In a normal
person, myocardial blood flow (fvlBF) increases ‘in proportion to the DIA (mm)
increase in myocardial oxygen demand. In a patient (Pt) with a fixed FIGURE 5. Relation between coronary artery diameter (DIA) and re-
obstruction (RI in Figure 1) d’ue to coronary artery disease (CAD), flow sistance (RES) to flow. Obstructive lesions of different lengths are de-
increases in responseto increased oxygen demand until the ceiling for picted by the 4 different curves; as length of the lesion increases, the
arteriolar dilatation (Rs in Figure 1) is reached. At this time, flow can resistance to flow increases at any given vessel diameter. However,
no longer increase despite the continued increase in myocardial oxygen because resistance is proportional to the fourth power of vessel di-
demand. A flow deficit results, thereby leading to myocardial ischemia ameter, vessel diameter is the preponderant influence on resistance
and angina pectoris. Reprinted with permission from Am J Cardiol.17 to ffok. Reprinted with permission from Am J Cardiol.17
major resistance to flow occurs in the small arteries and
arterioles. Because of the characteristics of the curve
relating vascular resistance to vessel diameter, it be-
comes clear why small changes in the diameter of a
normal epicardial vessel will little alter resistance to
flow, whereas small changes in vessels already narrowed
by atherosclerotic lesions will lead to marked changes
in resistance. Increasing the length of the lesion also
increases resistance to flow, but because the relation of
the length of the lesion to resistance is not exponential,
and the relation to vessel diameter is, the impact of the
length of a lesion on resistance is much less than the
impact of the diameter of a lesion.
Influence of Flow on Pressure Drop
Across a Stenosis and on Stenosis Resistance
One of the interesting aspects of atherosclerotic le-
sions is that even in the presence of a fixed anatomic
stenosis, resistance is not fixed.l-g Thus, pressure drops
(energy losses) across a stenosis are caused by viscous
losses (due to the friction that blood encounters as it
passes through the stenosis) and by the abrupt expan-
sion and resulting separation and turbulence of the flow
stream as it emerges from the stenosis. This can be ex-
pressed mathematically by the equation:
AP = (F x Q) + (S x Q2),
where F is a constant related to friction or viscous losses
and S is a constant relating to losses due to separation
or expansion (turbulence) of the flow stream. At low
flows, such as those that occur at rest, losses due to
viscous friction are predominant. At higher flows,
however, as with exercise, energy losses due to turbu-
lence are more important. As indicated in the equation,
ue to turbulence are related to the
square of flow. Hence, the relation between pressure loss
and flow is not linear but exponential. This is depicted
in Figure 6, which demonstrates the relation between
the pressure drop across a stenosis and coronary flow:
pressure drop increases in a curvilinear fashion with
increasing flow. It can be appreciated from Figure 6 that
because resistance to flow is the slope of the line relating
pressure to flow, resistance actually increases as flow
increases, despite the fact that there is no alteration in
the anatomic severity of the stenosis. Thus, as flow in-
creases so does resistance, and the influence of this
change in flow on resistance is linear. This can be de-
rived from the flow equations:
BP = (F X Q) + (S x Qs)
because
then
The increased pressure drop across a fixed stenosis
that occurs with increased flow has important conse-
quences. For example, Figure 7 depicts the influ
such a pressure drop on collateral flow. Figure
picts a situation in which 1 coronary artery is
occluded, and the myoca it has perfused is now
supplied by collaterals fe a coronary artery with a
moderate stenosis. The rioles of the collateral-

90%
(.07mm*)

FLOW

FIGURE 7. Influence of a partial stenosis on the driving pressure at the

origin of coronary collaterals. A depicts a totally occluded coronary
artery whose perfusion bed is supplied by collaterals from a vessel
without significant narrowing. B depicts the same situation, but the
vessel supplying the collaterals has a stenotic lesion. Graph depicts
the influence of increasing flow on the pressure drop across a stenotic
FLOW lesion. A vasodilator stimulus decreases resistance to flow in the region
FIGURE 6. Relation between change in pressure gradient (AR) across that is supplied by the normal or only partially stenotic vessel. Flow to
stenosis and change in flow. Curves are plotted for stenoses producing this area increases, but in the situation in which a partial stenosis of
30, 50, 70, 80 and 90% narrowing; the numbers in parentheses rep- the vessel feeding the collaterals exists, the small pressure drop across
resent luminal cross-sectional area, calculated on the basis of a normal the stenosis present under baseline conditions increases. If aortic
vessel diameter of 3 mm. Tangents to the curves (R) represent stenosis pressure does not increase, then the driving pressure across the cot-
resistance. Flow-related changes in resistance occur without changes lateral bed decreases in 8, but does not change appreciably in A. Hence,
in stenosis geometry. Reprinted with permission from Circ Res.*’ flow to the collateral dependent bed falls in
dependent bed are fully dilated by autoregulatory mands on the endocardium are greater than those on the
mechanisms, so that the total baseline resistance of this epicardium, the resistance vessels of the endocardium
bed is normal and ischemia is prevented. However, the (Ra) are more dilated than those of the epicardium (Rs).
arterioles supplied by the moderately stenotic artery In this situation, a vasodilator stimulus will decrease Rs
need only be minimally dilated to maintain baseline but will not alter Ra, because its vasodilator reserve is
resistance at normal levels. Thus, the vasodilator reserve already exhausted. This will result in a net decrease in
of this bed is preserved, and will exhibit a decrease in transmural resistance and, therefore, an increase in flow;
resistance in response to a vasodilator stimulus (such the increased flow, however, will be confined to the sub-
as exercise or the administration of a potent arteriolar epicardium, while the subendocardium will actually
dilator). The same vasodilator stimulus will produce experience a decrease in flow. These changes occur be-
little or no dilation in the collateral-fed arterioles, cause of the increased transmural flow, which causes an
however, because they are already maximally dilated. increased pressure drop across the stenosis, resulting
The resulting net decrease in resistance will increase in a lower driving pressure responsible for perfusing the
flow across the moderately stenotic lesion and, as is subepicardial and subendocardial vessels. The decrease
evident from Figure 6, the increase in flow will markedly in Rs will permit subepicardial flow to increase, but
increase the pressure drop across the stenosis. The because Rs did not fall, the decreased driving pressure
pressure just distal to the stenosis (Ps, Fig. 7B) will drop. will cause subendocardial flow to fall with resulting
Because this is the driving pressure for the collateral- ischemia.
dependent bed, and because resistance in that bed did
not fall, then flow to the collateral-dependent bed will Dynamic Coronary Obstruction
fall, thereby causing ischemia. Because resistance fell Studies over the past 10 years have unequivocally
in the bed supplied directly by the moderately stenosed documented the important role of dynamic alterations
artery (and was the cause of the increase in flow), flow in both large and small vessel coronary vascular resis-
to this bed will increase. This is the classic example of tance on altering coronary flow and coronary flow re-
a myocardial “steal.” serve. These dynamic alterations in coronary vascular
In Figure 7A there is no flow-limiting stenosis in the resistance have important clinical consequences.
vessel feeding the collaterals. The lack of such a stenosis Large vessel spasm: The seminal work of Maseri
means that when a vasodilator stimulus is present, and co-workers demonstrated that large vessel spasm
pressure at the head of the collaterals will not decrease; can decrease flow in either “normal” or stenotic large
thus, flow to the potentially ischemic bed will be coronary arteries, and thereby precipitate transient
maintained. episodes of myocardial ischemia.lOJ1 Although this
Figure 8 depicts a situation in which similar principles mechanism offered one pathophysiologic explanation of
explain how an “endocardial steal” can occur. A stenosis angina at rest, it could not account for the frequent oc-
is shown involving a vessel supplying the endocardium currence of variable threshold angina-an experience
and the epicardium. Because myocardial oxygen de- many patients have; on some days or times of the day
they have excellent exercise capacity, whereas at other
times, angina is precipitated at low levels of exercise. It
was subsequently shown that angina occurring during
exercise, particularly if associated with ST-segment
elevation, was on occasion associated with exercise-
induced narrowing of large coronary arteries.12J3 Ex-
ercise-induced coronary artery narrowing can theoret-
ically be caused either by active coronary vaso-
constriction or by passive coronary collapse.5-gJ4-16
Figure 9 depicts a large coronary artery with moderate
narrowing produced by a stenotic lesion. With exercise,
the arterioles dilate, thereby increasing flow across the
stenotic lesion (RI). As previously discussed, this in-
creased flow will lead to an increased pressure drop, the
magnitude of which relates to the severity of the stenosis
and the magnitude of the increase in flow (Fig. 6). It is
possible that the decrease in intraluminal pressure
might predispose to collapse of the artery, thereby in-
creasing the severity of stenosis and accounting for ex-
ercise-induced large vessel “spasm.” Any intervention
FIGURE 8. Effects of a stenosis on endocardial and epicardial flow. that directly leads to a fall in coronary perfusion pres-
Endocardial vessels are maximally dilated, whereas epicardial vessels
are not. Any vasodilator stimulus will augment transmural flow owing sure, as would occur with the administration of a vaso-
to dilation of subepicardial vessels. increase in flow will cause a greater dilator or following significant hemorrhage, might also
pressure drop across the stenosis. As long as the fall in resistance in lead to possible increases in stenotic resistance by this
subepicardial vessels is greater than the resulting fall in driving pressure, mechanism.5-gJP16 Exercise-induced coronary con-
flow will increase in subepicardial region. However, because suben-
docardial vessels are already maximally dilated, the fall in driving
striction or collapse undoubtedly explains some of the
pressure will not be accompanied by a fall in resistance. Hence, flow marked variations in exercise capacity experienced by
to subendocardial vessels will fall. many patients with angina.
 Another potential mechanism that could explain
variable threshold angina has been suggested. It was
hypothesized that subtle vasoconstrictor influences
playing on the large coronary arteries episodically
caused clinically significant alterations in coronary
vascular resistance.i7 Such alterations in coronary tone,
although not necessarily producing such profound
coronary vasoconstriction that angina at rest would be
precipitated, could be severe enough to interfere with
the normal augmentation in flow that occurs with ex-
ercise (Fig. 10). Thus, the concept of coronary spasm
was broadened-at one end of the spectrum, spasm is
so severe that it causes total or near total coronary ob-
struction resulting in angina at rest; at an intermediate
point of the spectrum, vasoconstriction is moderate,
leading to angina induced by low-level exercise; at the
other end of the spectrum, coronary tone might actually
diminish, with the resulting vasodilatation leading to
minimal impairment in exercise capacity. The influence
of such small changes in large vessel coronary diameter
on resistance to flow, especially in the presence of a
stenotic lesion, has been previously discussed and is il-
lustrated by the concepts depicted in Figure 5.
Constriction of small coronary arteries and de-
creased vasodilator reserve: Changes in vasocon-
strictor influences playing upon the large epicardial
coronary vessels undoubtedly account on occasion for
the varying thresholds of exertional angina seen in many
patients with coronary artery disease. However, we have
observed many patients with variable threshold angina
in whom the large coronary vessels were normal and did
not develop spasm in response to ergonovine or cold
pressor testing. This prompted us to measure regional
coronary blood flow and resistance to determine
whether the pain experienced by these patients might
FIGURE 9. Diagrammatic representation of vessel
myocardial flow increases. Under baseline conditions,
stenosis is modest and a large pressure gradient does not develop. With
a vasodilator intervention, pressure gradient across
creases. The resulting fail in intraluminal pressure may lead to collapse
of the vessel, thereby increasing the degree of stenosis.
be due to constriction of coronary vessels too small to
be imaged by angiography.isJg
We selected patients who had many of the compo-
nents suggestive of classic angina, except that there was
considerable variability relating to the intensity of
exertion that brought on the pain, and most patients
also experienced pain at rest. To exclude classic
Prinzmetal’s angina, we eliminated all patients exhib-
iting ST-segment elevations when electrocardiograms
were obtained during episodes of pain. Patients with
significant large vessel disease were specifically ex-
cluded to avoid the inaccuracies inherent in measuring
small changes in the caliber of stenotic vessels, which
despite even small magnitudes of change, could lead
to major alterations in coronary vascular resistance
(Fig. 5).
Great cardiac vein flow, reflecting flow through the
left anterior descending coronary artery, was measured
by a thermodilution catheter introduced into the cor-
onary sinus and advanced to the great cardiac vein. Flow
was determined under baseline conditions and during
pacing to increase myocardial oxygen demands; this was
achieved by pacing through a coronary sinus catheter
at an initial heart rate of 190 beats/min and increasing
by 10 beats/min increments at l-minute intervals up to
a heart rate of 150 beats/min. The measurements at rest
and with pacing were repeated during immersion of the
hand in ice water (cold pressor testing) and during er-
gonovine infusion. Arteriography of the left coronary
artery was performed in 2 views 90” apart, for a quan-
titative measurement of epicardial coronary artery
caliber.
We found that persons without chest pain during
pacing had large decreases in coronary resistance and
concomitant increases in great cardiac vein flow (Fig.
11). In contrast, these responses were markedly atten-
uated in those patients in whom pain developed. Er-
gonovine infusion resulted in the greatest number of
abnormal responses. Some patients actually experi-
enced pain at rest during ergonovine infusion that was
collapse when
flow across the
the stenosis in- FIGURE 10. How a given atherosclerotic lesion can cause angina at
rest, exercise-induced angina or no angina, depending on the underlying
vasoconstrictor tone of the coronary vessel.
 1°C A S;YMI-“SWM: t,WtHlMr-N I AL ANU GLINIGAL AWtGTS OF CORONARY VASOCONSTRICTION

associated with marked diminution in great cardiac vein constrictor influences or to primary disease of the small
flow and increase in calculated resistance. Patients who coronary arteries. However, it is also possible that in-
developed chest pain in response to pacing also exhib- adequate vasodilator reserve of the small coronary ar-
ited abnormalities of lactate metabolism, left ventric- teries can be due to abnormal myocardial compressive
ular end-diastolic pressure and left ventricular systolic forces. Thus, a primary abnormality in myocardial re-
function.1S20 These findings further substantiated the laxation leading to a retardation in the rate of diastolic
conclusion that the chest pain experienced by these relaxation, or the presence of increased left ventricular
patients, in whom small or no increases in coronary flow filling pressure due to decreased compliance (owing to
occurred during pacing, was indeed due to myocardial ischemia or certain cardiomyopathic processes), might
ischemia. The fact that the diameter of the large coro- increase myocardial wall tension during diastole and
nary arteries was essentially unaltered with pacing and thereby interfere with coronary fl0w.2~
during vasoconstrictor maneuvers indicates that the site In summary, the normal adaptive mechanisms closely
that limited vasodilator reserve (or that actually con- regulate coronary blood flow so that myocardial oxygen
stricted) was located in coronary arteries too small to delivery is tightly coupled to myocardial oxygen de-
be imaged angiographically. Hence, abnormalities at the mand. Fixed stenoses of the epicardial coronary vessels,
level of small coronary arteries can contribute to the or dynamic changes in coronary resistance that occur
precipitation of myocardial ischemia, either by dy- either at the epicardial or small vessel level, interfere
namically increasing coronary resistance in response to with these normal adaptive responses. The mechanisms
vasoconstrictor influences, or by restricting vasodilator responsible for dynamic alterations in coronary resis-
reserve and thus the potential to augment flow. These tance are complex, but must be considered if a com-
abnormalities would predispose to the development of prehensive understanding of the factors leading to
ischemia during interventions or activities that increase myocardial ischemia and angina pectoris is to be
myocardial oxygen requirements. achieved.
Myocardial compressive forces: Abnormal flow
reserve of small coronary arteries can be due to vaso- References
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