Download Myocardial Blood Flow in Coronary Artery Disease

Myocardial Blood Flow in Coronary Artery Disease
Effect of Right Atrial Pacing and Nitroglycerin
SUZANNE B. KNOEBEL, M.D., PAUL L. MCHENRY, M.D.,
ANTHONY J. BONNER, M.D., AND JOHN F. PHILLIPS, M.D.
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SUMMARY
Sixteen patients, 10 with significant three-vessel coronary artery disease (>50% occlusion of each
vessel) and six without coronary disease, had nutrient myocardial blood flow, cardiac output, pressure time/ min and arterial pressure determinations at rest, with atrial pacing
and with right atrial pacing plus nitroglycerin. In the patients with coronary disease, nutrient myocardial blood decreased an average of 16% (P < 0.001) with pacing alone but
increased by 22% (P < 0.001) from the pacing flows with the addition of 0.4 mg sublingual nitroglycerin at the same pacing rate. The directional changes in myocardial blood
flow were unrelated to perfusion pressure or pressure work. In the patients without coronary disease, opposite effects were observed. With right atrial pacing, nutrient myocardial blood flow increased by 23% (P < 0.02). With the addition of nitroglycerin, myocardial blood flow decreased by
15% (P < 0.02). These changes were directionally related to changes in pressure-work of the heart
It is suggested that the findings in this study are consistent with observations made in the experimental animal which indicate that the effect of nitroglycerin may be partly due to a redistribution of myocardial blood flow.
Additional Indexing Words:
Autoregulation
Coincidence technic
S4Rubidium
Nutrient blood flow
IN THE PAST few years a number of studies
have been reported utilizing acceleration of the
heart rate by right atrial pacing as a stress
intervention to study the hemodynamic, metabolic,
and coronary flow characteristics in patients with
coronary artery disease.' 14 The intervention has
been of considerable interest because it is relatively
safe, repeatable, and defines a threshold in terms of
the tension-time index, pressure time/min, or triple
product,6 having fewer independent variables than
exercise or other forms of stress testing.4 5 9 13 The
studies have demonstrated manifestations of ischemia such as impaired left ventricular function,
electrocardiographic alterations, and lactate pro-
Perfusion pressure
duction. More recently, demonstrations of coronary
flow inadequacy with atrial pacing in coronary
artery disease have also been reported.15' 16
In addition, nitroglycerin has been shown to
increase the threshold to right atrial pacing in that
indirect reflections of myocardial blood flow deficiency have been reversed at identical pacing rates
through the concomitant use of nitroglycerin.4' 17, 18
Whether the effect of nitroglycerin in this situation
is manifested by reducing myocardial oxygen
requirement or by altering the distribution of
myocardial blood flow is unresolved.'9 Many of the
problems concerning the effect of nitroglycerin are
compounded by the varying methods used to
determine myocardial blood flow. Some methods
measure total coronary flow, not necessarily nutrient flow, some methods may be relatively insensitive to poorly perfused areas, some technics
measure regional perfusion, and so forth.20-23 This
study was designed to evaluate alteration in
nutrient myocardial blood flow produced by
sublingual nitroglycerin administered during right
atrial pacing in patients with three-vessel coronary
artery disease, as compared with patients without
coronary artery disease. Nutrient myocardial blood
From the Department of Medicine, Indiana University
School of Medicine, the Krannert Institute of Cardiology,
and Marion County General Hospital, Indianapolis, Indiana.
Supported in part by the Herman C. Krannert Fund, U. S.
Public Health Service Grants HL-06308, HL-05363, and
HL-05749, the Indiana Heart Association, and the
Northwest Indiana Heart Association.
Address for reprints: Suzanne B. Knoebel, M.D., 1100
West Michigan Street, Indianapolis, Indiana 46202.
Received August 28, 1972; revision accepted for
publication November 30, 1972.
690
Circulation, Volume XLVII, April 1973
691
MYOCARDIAL BLOOD FLOW IN CAD
flow
measured utilizing a coincidence counting
and single bolus of 84Rb.24 25
was
system
Material and Methods
Sixteen patients undergoing selective coronary cinearteriographic studies for diagnosis or evaluation of the
severity of coronary arteriosclerotic occlusive disease
had myocardial blood flow determinations at rest, with
right atrial pacing, and with right atrial pacing
concomitant with the administration of sublingual
nitroglycerin. The studies were performed just prior to
the arteriographic evaluation.
All studies were performed in the morning with the
patients in a fasting state and without sedation.
Measurements were made with patients in the supine
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position.
A bipolar pacing catheter was passed through the
basilic vein, positioned in the right atrium so that its tip
was in contact with the high lateral wall, and connected
to a battery-powered pacemaker (Medtronic). A short
polyethylene catheter (approximately 18 gauge) was
introduced percutaneously into the right femoral
artery.
Blood pressure was measured via the indwelling
catheter in the femoral artery, connected to a Statham
P23D strain-gauge transducer and recorded on a
Sanborn recorder (model 150). The mean arterial
pressure was obtained by electric integration and the
mean systolic arterial pressure by planimetric integration. Pressure time/min, expressed in mm Hg-secs/min,
was obtained as the product of systolic mean arterial
pressure, heart rate, and systolic ejection period.
Systolic ejection period, in seconds, was measured from
the pressure records as the time interval between the
onset of the femoral artery pulse and the dicrotic notch,
and was expressed as the average figure of at least six
beats taken at the extremes of respiratory fluctuation.
Heart rate was measured from a simultaneously
recorded electrocardiogram. The cardiac output was
determined using 84RbCl as the indicator.26
Myocardial blood flow, in ml/min per total heart,
was calculated using the formula: MBF= q(t)/ f-0AO
(t)dt where q(t) is the myocardial uptake of 84RbC]
as measured by the coincidence counting system and
f ,A,, (t) dt
represents the concentration of the
isotope in arterial blood during the first circulation,
determined by extrapolation after recirculation begins.
The theoretic basis of this formulation, experimental
verification, and critique have been reported in
-
detail.25'
27
Control measurements were made during sinus
rhythm, after which pacing was begun. The heart rate
was gradually elevated to the point where 1: 1 A-V
conduction could just be maintained or angina
intervened. The maximal heart rate achieved was
maintained for 3 min before and during the taking of
repeat measurements unless angina intervened. If
angina intervened, the pacing was continued for the
time period necessary to make the myocardial blood
flow measurement (45 sec). Following a recovery
period of 10 min, pacing was instituted at the same rate
as on the previous determination and concomitantly 0.4
mg nitroglycerin was given sublingually. Repeat
Circulation, Volume XLVII, April 1973
measurements were made at the precise time as the
first stress measurement.
After completion of the myocardial blo)d flow and
hemodynamic determinations coronary cineangiography
was performed. Multiple oblique views were obtained
using renographic contrast media. Injections were made
before and after administration of sublingual nitrates.
Recording was performed with 35-mm Double-X film
developed in Ethol-90. A Phillips 6-in image intensifier
was utilized with a 100-mm lens at 64 frames/sec.
Only patients whose cineangiograms were of good
quality in multiple projections of all three major coronary vessels were included in this study. Coronary arterial lesions were classified as follows: Each of the
three major coronary vessels (right, left anterior descending, and circumflex) was assigned a value of 100.
A value of 200 was assigned to the left mainstem coronary artery. The number of vessels involved was then
determined and the percentage of each vessel which remained open was estimated in increments of 25%. In
the case of branch stenosis, the degree of occlusion was
estimated according to the technic of Rowe et al.20 For
example, if the anterior descending artery bifurcated,
giving off a branch about 50% of the size of the parent
vessel and if this vessel were 50% occluded, the estimated occlusion of the anterior descending vessel would
be equivalent to 25% occlusion of the anterior descending coronary artery. A final coronary artery index was
then based on the estimated percentage of lumen of all
three vessels remaining open (300 equaling no occlusive
disease). The cinearteriograms were interpreted independently by three investigators without availability of
the physiologic data. Ten consecutive patients with
coronary artery indices of 50 or less and six patients
without coronary artery disease were included in this
study. All data analyzed as the significances of the
difference between the means of paired data.
Results
Coronary Artery Disease Patients
None of the 10 patients with coronary artery
disease and coronary artery indices of 50 or less
was able to increase myocardial blood flow
significantly with pacing to an average rate of 131
beats/min (range 120-158) (table 1). Seven of the
10 experienced angina with pacing. All of these
patients experienced pain after at least 2 min of
pacing so that the disparity between pacing times
for patients with and without angina was minimal.
The average myocardial blood flow for the group
changed from 207 ± 53 ml/min, representing 4% of
the cardiac output at rest, to 178 ± 50 ml/min, 3.4%
of the cardiac output, with atrial pacing
(P < 0.001). Pressure time/min rose 34% with
pacing (P <0.001). Mean arterial blood pressure
increased from an average of 98± 14 to 107±22
mm Hg (P < 0.05), and the diastolic pressure from
75 ± 10 to 90 ± 17 mm Hg (P < 0.01). There was a
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negative correlation between the change in myocardial blood flow and diastolic blood pressure
(r=0.6783; P <0.05).
With pacing to the same rate but with 0.4 mg
sublingual nitroglycerin administered at the onset
of pacing, myocardial blood flow increased significantly (P < 0.001), as compared with pacing alone,
from an average of 178 ± 50 to 217 + 48 ml/min.
The change was not significantly different from that
of the resting state. The pacing plus nitroglycerin
flows represented 3.4 and 4.2% of the cardiac
output, respectively. Pressure time/min decreased
13% (P < 0.001), mean blood pressure and diastolic
blood pressure decreased 12% and 9%, respectively
(P < 0.02), with pacing and nitroglycerin.
Five patients with three-vessel coronary artery
disease had previously been studied with two
pacing myocardial blood flow determinations separated by a 3-5-min time interval. This was done to
determine if a first pacing had, in some manner,
influenced a second pacing result, and, thus,
nullified the nitroglycerin results. There was no
significant change in myocardial blood flow, in this
group, between the two pacing flow determinations.
There were no significant changes in cardiac
output with pacing or with pacing and nitroglycerin.
Patients without Coronary Disease
In the six patients without coronary occlusive
disease, myocardial blood flow increased 23%
(P < 0.02) from a control average of 235 ml/min to
288 ml/min, representing 5% and 6% of the cardiac
output, respectively, with right atrial pacing to an
average rate of 133 beats/min (table 2). Cardiac
output increased insignificantly with pacing from
4.7 liters/min to 4.8 liters/min average for the
group. Pressure time/min increased significantly by
21% (P < 0.01) from 2598 to 3168 mm Hg-sec/min.
The mean arterial and diastolic blood pressures
increased insignificantly with pacing.
With atrial pacing and nitroglycerin, myocardial
blood flow decreased by 15% (P<0.01) from 288
ml/min to 245 ml/min. This was a change from 6%
of the cardiac output to 5.7% of the cardiac output.
The cardiac output decreased from 4.8 liters/min to
4.3 liters/min, a significant change (P <0.02).
There were no significant changes in blood
pressure.
A graphic presentation of the changes in
myocardial blood flow with pacing plus nitroglycerin for both groups is shown in figure 1.
Circulation, Volume XLVII, April 1973
MYC)CARDIAL BLOOD FLOW IN CAD
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The hemodynamic data from this study are
similar to those reported in a number of other
studies. Right atrial pacing has been demonstrated
to increase pressure time/min and not to affect
cardiac output significantly.2 4 7 Nitroglycerin decreases pressure time/min with pacing, reduces
systemic blood pressure, and probably results in
decreased ventricular dimensions.17' 18, 28 In addition, nitroglycerin seems to decrease myocardial
blood flow in normal subjects if the pressure timework of the heart also decreases.29 30 This has been
taken to suggest that nitroglycerin does not affect
autoregulatory mechanisms in the normal heart.29 31
Further comparison with previous studies is probably not warranted as there is great variation in
experimental design, amount, and route of nitroglycerin administration, times at which measurements
were made, sedation used and, in particular,
methods of determination of coronary and myocardial blood flow.
The validity of the myocardial blood flow
changes demonstrated in this study needs to be
assessed. The possible problems inherent in the
coincidence technic itself have been previously
discussed at length.'5 25-27 Basically, the ability to
quantitate flows has been questioned, changing
extraction ratios have been an issue, and clearance
dependency on flow rate is a consideration. For
these reasons we have not attempted to place
significance on absolute flows in ml/min, but have
relied on directional changes; and directional
changes in coronary patients have been interpreted
only as compared to patients without large-vessel
coronary artery disease.
While the exact mechanisms for the reduction in
nutrient myocardial blood flow with right atrial
pacing and the increase with sublingual nitroglycerin are not resolved by the study, the following
considerations may be applicable. The same considerations also may be a partial explanation for the
discrepancy between these data and data from
previous studies measuring coronary blood flow
with other technics. Further resolution of the
mechanisms operative in patients with coronary
artery disease, in particular, will come through the
use of technics measuring regional flow more
directly than does the coincidence system. A
characteristic of the coincidence system for measuring myocardial blood flow is that detection of a
decrease in regional perfusion, if of sufficient size, is
possible as total myocardial uptake of isotope
KNOEBEL ET AL.
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PACING
PACING
NITROGLYCERIN
PACING
PACING
NITROGLYCERIN
Figure 1
(Left) The percent change in myocardial blood flow with right atrial pacing, and pacing and nBitroglycerin, in
patients with three-v;essel coronary art;ery disease. (Right) The changes induced by the same interventions in patients without coronary artery disease.
decreases.15, 32 Thus, the coincidence system may
reflect alterations in regional perfusion. Other technics measuring single-vessel flow or dominated by
single-vessel flow might register no increase (fixed
flow) with an intervention which acts primarily by
redistribution of flow or an actual increase in flow
through nonoccluded vessels.15'23 With these considerations in mind, we propose that our data support the concept that, in the patient with coronary
artery disease, when ischemia is caused by an increase in myocardial oxygen requirement with
atrial pacing, a redistribution of blood flow
occurs, the nutritional flow to the endocardium
being limited by flow in the large conducting
vessels.33 The decreased nutritional flow to the
endocardium, by adding a zero count to the
myocardial uptake of rubidium, results in the
coincidence system measuring a decreased flow.
Nitroglycerin, in addition to reducing cardiac work
so that a better ratio exists between nutritional
circulation toi the endocardium and requirement, also
results in a redistribution of nutritional blood
supply,33 reflected by an increased flow measured
by the coincidence system.
Data from experimental animal studies utilizing
microsphere injection technics and intramyocardial
oxygen tension measurements34-37 are in accord
with the concepts outlined above. It has been
demonstrated that, in addition to a reduction in
total blood flow following acute experimental
coronary artery occlusion, there is also a disproportionate reduction in subendocardial flow within the
ischemic area.34 The possible mechanisms for this
altered flow pattern have been discussed by Becker
and Pitt,35 including a change in resistance gradient
between endo- and epicardium, a possible perfusion
pressure drop in perforating vessels, and an increase
in extravascular compressive forces, all essentially
mechanical effects following ischemia. Another
model proposed by McGregor and Fam3' also
warrants consideration and is, perhaps, more
appropriate for the chronic state. In their model, a
decrease in resistance at the arteriolar level of
nonoccluded vessels when oxygen requirement is
increased, might result in a decrease in blood flow
to a portion of the myocardium previously supplied
by that artery through collaterals, a "coronary steal"
syndrome. Whichever mechanism, i.e., mechanical
Circulation, Volume XLVII, April 1973
MYOCARDIAL BLOOD FLOW IN CAD
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effects as proposed by Becker and Pitt or "coronary
steal" as proposed by McGregor and Fam, is
operative in patients with coronary disease, nitroglycerin could result in a redistribution of flow into
an ischemic area as has been shown in the
experimental animal.4-3 By decreasing myocardial
oxygen demands through reduction in arterial
pressulres, wall tension, and ventricular volume, the
increased extravascular compressive forces caused
by ischemia could be reversed and flow reestablished. Or, by allowing vasoconstriction to again
maintain in nonoccluded vessels, the "steal" might
be eliminated by reestablishing resting pressure
relationships.
Another possibility is that nitroglycerin may
dilate collateral vessels in coronary patients and,
thus, partially decrease the resistance quantum of
the proximal occlusive lesions, effectively allowing a
greater coronary reserve.'9 38 Nitroglycerin has
been shown to dilate collateral vessels and increase
flow to areas supplied by such vessels.38 However, it
would seem that if the arteriolar bed were fully
dilated because of increased oxygen demand by
right atrial pacing, or if extravascular resistance
were increased in an ischemic area, an increased
volume of flow through collaterals would simply
continue to traverse the path of least resistance and
would not necessarily become nutrient flow. It is
possible, however, that nitroglycerin by decreasing
wall tension could permit collateral flow, which had
been prevented by the ischemic changes, to
resume33 and, perhaps, be augmented.39
The questions raised may prove to have some
clinical relevance. Regardless of the mechanisms
involved, the diseased coronary circulation does not
appear to be entirely a passive one. It is not a
perfusion pressure-dependent system, in the sense
of epicardial vessel perfusion pressure, within
normal ranges of blood pressure. The nutrient
myocardial blood flow can be manipulated through
the use of drugs which either decrease the pressure
time/min, redistribute myocardial blood flow, or,
perhaps, increase collateral flow. If, for example, it
were necessary to artificially increase heart rate in
patients with coronary artery disease for the control
of ventricular tachycardia or other tachyarrhythmia,
it might be possible to "protect" the blood supply to
the myocardium through the concomitant use of an
agent such as nitroglycerin. Other combinations of
interventions could be similarly considered. Elevation of arterial blood pressure designed to
increase coronary perfusion pressure might rather
Circulation, Volume XLVII, April 1973
695
increase pressure work and myocardial consumption to the point where coronary reserve would be
exceeded. These considerations are of particular
importance in dealing with patients with myocardial infarction or impending infarction where a
prime concern is in preserving as much myocardial
blood flow as possible in order to reduce to a
minimum the area of myocardial ischemia. Each
patient, however, should be assessed individually.
Not all of our patients had angina induced by
pacing nor did nitroglycerin consistently relieve
induced angina. Other investigators have observed
similar variability.'2 The relationship between
myocardial oxygen demand induced by any particular stress, the mechanisms by which various agents
exert influence on collateral vessels, and work of the
heart may vary considerably from patient to
patient. It is the algebraic sum of all effects that is
probably important and may account for differing
clinical responses.
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Circulation, Volume XLVII, April 1973
Myocardial Blood Flow in Coronary Artery Disease: Effect of Right Atrial Pacing and
Nitroglycerin
SUZANNE B. KNOEBEL, PAUL L. MCHENRY, ANTHONY J. BONNER and JOHN F. PHILLIPS
Circulation. 1973;47:690-696
doi: 10.1161/01.CIR.47.4.690
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