Download Relation between regional function and coronary blood - AJP

Am J Physiol Heart Circ Physiol
279: H3058–H3064, 2000.
Relation between regional function and coronary blood
flow reserve in multivessel coronary artery stenosis
JIAN-PING BIN, ROBERT A. PELBERG, KEVIN WEI, MATTHEW COGGINS,
N. CRAIG GOODMAN, AND SANJIV KAUL
Cardiac Imaging Center, Cardiovascular Division, University of Virginia,
Charlottesville, Virginia 22908
Received 24 January 2000; accepted in final form 13 July 2000
resting regional dysfunction; dobutamine echocardiography
percent wall thickening (%WT) is
reduced at rest only when resting myocardial blood
flow (MBF) is reduced (5, 30). In the setting of chronic
coronary stenoses, however, resting %WT can be abnormal despite normal resting MBF (24, 29). Although
this phenomenon has been described when collateral
vessels are well formed (24, 29), it is also seen when
collateral flow has not yet developed (2), the mechanism of which is not clear.
In addition to coronary vasodilators that increase
MBF by their direct action on arteriolar smooth muscle
(20, 23), catecholamines (particularly dobutamine)
have also been used for the detection of coronary stenoses (9, 22, 23). It is believed that these agents inIN THE ACUTE SETTING
Address for reprint requests and other correspondence: S. Kaul,
Cardiovascular Division, Univ. of Virginia, Medical Center, Box 158,
Charlottesville, VA 22908 (E-mail: [email protected]).
H3058
crease myocardial oxygen demand (28), which, in the
presence of coronary stenosis, results in abnormal
%WT due to a lack of a concomitant increase in MBF.
There is a lack of experimental data validating this
assumption for chronic coronary stenoses. Similarly,
whereas dobutamine has also been used successfully to
assess myocardial viability in patients with chronic
coronary stenoses and reduced %WT (1, 19, 21, 29),
there are few data regarding the pathophysiological
basis for its use.
We have developed a closed-chest canine model of
multivessel chronic coronary stenoses by placing
Ameroid constrictors on proximal arteries supplying
the left ventricle (LV) (2). Between the first and second
week after placement of stenoses, MBF is normal, but
%WT may be reduced. Later on, MBF may decline or
remain normal depending upon the degree of collateral
vessel development. In either case, %WT remains
markedly reduced (2). In this study, we examined regional MBF and %WT between 1 to 2 wk after Ameroid
constrictor placement and before collateral development.
We postulated that, with a noncritical chronic coronary stenosis in the absence of infarction and before
collateral development, reduced resting %WT is caused
by abnormal MBF reserve. We also postulated that this
abnormal MBF reserve is also responsible for the “biphasic response” seen on catecholamine stimulation
(22). Additionally, in this setting, the increase in %WT
during low-dose dobutamine occurs (1, 21) because
some degree of MBF reserve is still present. Thus our
unifying hypothesis was that when resting MBF is
normal in the setting of chronic coronary stenosis,
regional function at rest and during dobutamine are
separate manifestations of the same phenomenon:
MBF reserve.
METHODS
Animal preparation. The study protocol was approved by
the Animal Research Committee at the University of Virginia and conformed to the American Heart Association
Guidelines for the Use of Animals in Research. Fifteen adult
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734
solely to indicate this fact.
0363-6135/00 $5.00 Copyright © 2000 the American Physiological Society
http://www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.2 on May 12, 2017
Bin, Jian-Ping, Robert A. Pelberg, Kevin Wei, Matthew Coggins, N. Craig Goodman, and Sanjiv Kaul.
Relation between regional function and coronary blood flow
reserve in multivessel coronary artery stenosis. Am J Physiol
Heart Circ Physiol 279: H3058–H3064, 2000.—In the setting
of chronic coronary stenoses, percent wall thickening (%WT)
both at rest and during catecholamine stimulation can be
abnormal despite normal resting myocardial blood flow
(MBF). We hypothesized that this phenomenon is related to
abnormal MBF reserve. Accordingly, 15 dogs were studied
between 7 and 10 days after placement of Ameroid constrictors around the proximal coronary arteries and their major
branches, at a time when collateral development had not yet
occurred. %WT and MBF were measured at rest, after 0.56
mg/kg of dipyridamole, and at incremental doses of dobutamine (5–40 ␮g 䡠 kg⫺1 䡠 min⫺1). Resting %WT and MBF were
normal in all four sham dogs. Resting transmural MBF was
normal in all segments in the 11 study dogs, despite reduced
(⫺2 SD of normal) %WT (⬍30%) in 40 of 82 segments. MBF
reserve was reduced (⬍3) in segments with reduced %WT,
and a close coupling was noted between resting %WT and
MBF reserve. All segments showed an increase in %WT with
dobutamine up to a dose of 20 ␮g 䡠 kg⫺1 䡠 min⫺1, above which
those with abnormal endocardial MBF reserve showed a
“biphasic” response. It is concluded that, in the presence of
chronic coronary stenoses, abnormalities in resting %WT as
well as inducible reduction in %WT during pharmacological
stress are related to the degree of abnormal MBF reserve.
REGIONAL FLOW-FUNCTION RELATIONS IN CHRONIC CORONARY STENOSIS
and the right ventricular free wall was defined over the
epicardium in each frame, and 100 equidistant chords between the two contours were generated starting at this point.
Each chord represented the shortest distance between the
epicardial and endocardial contours.
The observer then selected the myocardial regions (septal,
anterior, lateral, and inferior). Plots of %WT over the entire
systolic contraction sequence in the central 75% of each
region were then automatically generated, with time represented in deciles. Maximal thickening was selected from each
plot to represent %WT, which was defined as reduced when it
was less than mean ⫺ 2 SD of that in the normal myocardium
(⬍30%). The normal myocardium was defined as the anterior
interventricular septum at the upper papillary muscle level
because this region is supplied by the first septal perforator
artery, which was always proximal to the site the Ameroid
constrictor on the LAD.
Radiolabeled microsphere-derived MBF measurements.
Four sets of radiolabeled microspheres were used in each
animal to derive regional MBF (10). Approximately 2 ⫻ 106
11-␮m radiolabeled microspheres (DuPont Medical Products,
Wilmington, DE) were suspended in 4 ml of normal saline0.01% Tween 80 solution and injected into the left atrium
over 20 s. This number allows ⬎1,000 microspheres to be
sampled in each tissue sample when resting MBF is normal
or increased. Reference samples were withdrawn from the
femoral artery over 130 s with a constant rate withdrawal
pump (Harvard Apparatus, model 944, South Natick, MA).
The postmortem heart slices corresponding to the echocardiographic images were cut into 16 wedge-shaped pieces.
Each piece was further divided into epicardial, midmyocardial, and endocardial portions. The tissue and arterial reference samples were counted in a well counter with a multichannel analyzer (model 1282, LKB Wallac). Corrections
were made for activity spill-over from one window to the next
using a set of simultaneous equations programmed on a
computer (10).
MBF to each sample was calculated by the equation Qm ⫽
(Cm 䡠 Qr)/Cr, where Qm is flow (in ml/min), Cm are the tissue
counts, Qr is the rate of arterial blood withdrawal (in ml/
min), and Cr are the counts in the reference sample. Transmural MBF (in ml 䡠 min⫺1 䡠 g⫺1) to each segment was derived
by dividing the sum of MBF to individual segments by their
combined weight. Transmural MBF within each region (septal, anterior, lateral, and inferior) was calculated by averaging the transmural MBF in the segments within the central
75% of that region. Average endocardial and epicardial MBF
were similarly calculated. MBF was considered to be normal
in the upper septal region because this region is not affected
by placement of the Ameroid constrictor on the LAD coronary
artery.
Experimental protocol. In the four sham dogs, MBF and
%WT data were acquired at rest 7 days after placement of
Ameroid constrictor, after which they were euthanized. In
the 11 study dogs, data were acquired between 7 and 10 days
after surgery. Whereas MBF was expected to be normal and
no collaterals were expected to have developed in either
group of dogs, %WT was also expected to be normal in the
sham dogs (2). For data acquisition, dogs were heavily sedated with a single dose of 20 mg/kg fentanyl and a continuous infusion of 0.5 ml/min etomidate. The dogs were paralyzed with 300 ␮g/kg atracurium to obtain the same imaging
planes at each examination. They were then placed on their
left side, intubated, and ventilated on room air using a
respirator pump, which was set to maintain arterial blood
gases in the physiological range.
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.2 on May 12, 2017
mongrel dogs were used in this study. They were given 75 mg
of aspirin daily starting 3 days before surgery, which was
continued until euthanasia. Gentamicin (80 mg) and cefazolin (1 g) were administered intravenously just before surgery,
and the latter was given twice daily for 5 days after surgery
or longer if infection developed.
Surgery was performed in a sterile operating room. Anesthesia was induced with 300 ␮g/kg diazepam, 20 ␮g/kg fentanyl, and 400 ␮g/kg etomidate administered intravenously
and was maintained with a mixture of 1–1.5% isoflurane,
oxygen, and air. Arterial blood gases were analyzed every
hour, and the respiratory rate was adjusted to maintain them
within the physiological range. The electrocardiogram and
pulse oximetry were monitored throughout the operation. A
6-Fr indwelling catheter was placed in a femoral artery
through a groin incision and was used for arterial pressure
monitoring as well as withdrawal of samples for blood gas
and radiolabeled microspheres. After the catheter was secured in place with silk ties and its ends were capped with a
rubber injection port, the catheter was buried subcutaneously, and the groin incision was closed in layers.
Skeletal muscle paralysis was induced with 300 ␮g/kg of
atracurium, and a left lateral thoracotomy was performed.
The heart was suspended in a pericardial cradle, and the
proximal portions of the left anterior descending (LAD) and
left circumflex (LCx) coronary arteries, as well as any large
branches of these arteries, were dissected free from the
surrounding tissue. In 11 dogs, up to four appropriately sized
Ameroid constrictors (Medical Research & Manufacturing)
were placed around all the vessels, whereas in four dogs
(controls) they were placed on either the LAD or LCx coronary arteries. %WT was assessed visually after placement of
each Ameroid constrictor using direct epicardial echocardiography and was confirmed to be normal in all dogs. A 6-Fr
indwelling catheter was inserted in the left atrium, secured
in place with prolene sutures, capped off with a rubber
injection port, and then buried subcutaneously in the dorsum. The pericardium and chest were closed. The animal was
then revived and transferred to an observation area in the
vivarium.
Hemodynamic data. The femoral arterial and left atrial
catheters were accessed transcutaneously and connected to
fluid-filled transducers (model 1295A, Agilent Technologies)
via pressure tubing. The transducers were connected to a
multichannel recorder (model 4568C, Agilent Technologies),
which was connected to an 80386-based personal computer
(model 2531, DTK) through an eight-channel analog-to-digital converter (DAS 16/16F, Keithley-Metrabyte). Mean aortic
and left atrial pressures were digitally sampled using the
Labtech Notebook (Laboratory Technologies) and displayed
in real time during each protocol stage.
Wall thickening analysis. Regional %WT was measured
from real-time echocardiographic images obtained at two
short-axis planes (upper and lower papillary muscle levels).
A digital echocardiographic system with harmonic imaging
capabilities (3,000 Cv; Advanced Technology Laboratories,
Bothell, WA) was used. Data were acquired in real time and
stored on videotape for later analysis.
Images were transferred from videotape to a dedicated
image analysis computer. A special regional wall thickening
analysis software was used, which has been described by
Sklenar and co-workers previously (27). Several endocardial
and epicardial targets were defined by the observer in each
frame from end diastole to end systole. These points were
automatically connected using cubic-spline interpolation to
derive epicardial and endocardial contours. To correct for
systolic cardiac rotation, the junction of the posterior LV wall
H3059
H3060
REGIONAL FLOW-FUNCTION RELATIONS IN CHRONIC CORONARY STENOSIS
RESULTS
During surgery as well as the subsequent anesthesia, the average pH in all dogs was 7.37 ⫾ 0.01, PCO2
was 37 ⫾ 1.3 mmHg, PO2 was 93 ⫾ 2.4 mmHg, and O2
saturation was 97% ⫾ 1.0%. None of the dogs showed
clinical evidence of heart failure at the time of euthanasia. Postmortem, no heart slice showed evidence of
infarction on tissue staining. In all four sham dogs,
%WT was normal at rest in both LAD and LCx coronary artery beds, despite placement of an Ameroid
constrictor on one of the arteries. Resting %WT ranged
from 30 to 34%, and transmural MBF ranged from 1.0
to 1.4 ml 䡠 min⫺1 䡠 g⫺1 in regions supplied by normal
arteries. These same values ranged from 30 to 38% and
from 0.9 to 1.4 ml 䡠 min⫺1 䡠 g⫺1 in beds supplied by an
artery on which a constrictor had been placed. Thus
placement of Ameroid constrictors per se and their
presence for up to 1 wk had no effect on resting %WT or
MBF.
In the 11 study dogs, resting transmural MBF was
normal in all segments, whereas transmural MBF reserve was abnormal (⬍3) in 42 of 88 segments (8
segments in each dog, 4 each at the upper and lower
papillary muscle levels) analyzed for the dipyridamole
stage. The interventricular septal segment at the upper papillary muscle level (proximal to the LAD artery
constrictor) showed a transmural MBF reserve of ⬎3 in
all dogs. The resting MBF in this segment was similar
to that of other segments analyzed. Because of artifacts, six myocardial segments could not be analyzed
for %WT. Of the 82 myocardial segments analyzed,
%WT was reduced at rest (⬍30%) in 40 segments,
whereas it was normal in 42 segments. Mild global
dysfunction was noted in these dogs. The end-systolic
dimension was slightly (P ⬍ 0.05) increased on postoperative days 7–10 (3.4 ⫾ 0.22 cm) compared with baseline (3.2 ⫾ 0.12 cm). The end-diastolic dimension, however, was unchanged (4.3 ⫾ 0.22 vs. 4.4 ⫾ 0.32 cm).
There were no changes in heart rate or arterial
pressure at rest between baseline and postoperative
days 7–10. Even though dipyridamole caused mild
systemic hypotension and reflex tachycardia, the double product remained unchanged compared with baseline (Table 1). As expected, incremental doses of dobutamine caused increases in heart rate and double
product without affecting systemic pressure (Table 1).
The unchanged resting heart rate and the response to
dobutamine implied no significant ␤-adrenergic downregulation.
MBF and %WT. Table 2 presents the results of MBF
at rest and after dipyridamole in all segments. Irrespective of %WT, resting transmural MBF was normal
Table 1. Hemodynamic and %WT changes induced by dipyridamole and dobutamine
%WT at Rest
Stage
HR,
beats/min
AoP,
mmHg
Double
Product
Normal (n ⫽ 42)
Reduced (n ⫽ 40)
Resting
Dipyridamole (0.56 mg/kg)
Dobutamine (5 ␮g 䡠 kg⫺1 䡠 min⫺1)
Dobutamine (10 ␮g 䡠 kg⫺1 䡠 min⫺1)
Dobutamine (20 ␮g 䡠 kg⫺1 䡠 min⫺1)
Dobutamine (30 ␮g 䡠 kg⫺1 䡠 min⫺1)
Dobutamine (40 ␮g 䡠 kg⫺1 䡠 min⫺1)
76 ⫾ 18
104 ⫾ 15†
85 ⫾ 17
99 ⫾ 15
120 ⫾ 14‡
129 ⫾ 15‡
144 ⫾ 15‡§
87 ⫾ 14
74 ⫾ 11†
85 ⫾ 12
90 ⫾ 11
92 ⫾ 13
97 ⫾ 13
89 ⫾ 11
67 ⫾ 22
77 ⫾ 15
73 ⫾ 21
89 ⫾ 19
111 ⫾ 23‡
125 ⫾ 26‡
129 ⫾ 16‡
34 ⫾ 2
37 ⫾ 5†
37 ⫾ 3
43 ⫾ 3‡
49 ⫾ 4‡
49 ⫾ 10‡
43 ⫾ 14‡§
23 ⫾ 5
23 ⫾ 8
25 ⫾ 6
29 ⫾ 8‡
36 ⫾ 9‡
31 ⫾ 13‡
23 ⫾ 9§
Values are means ⫾ SD; n represents the number of segments in each group. %WT, percent wall thickening; HR, heart rate; AoP, mean
aortic pressure. The double product was found with the equation (HR 䡠 AoP)/100. *P ⬍ 0.0001 compared with segments with normal resting
function for all stages; †P ⬍ 0.05 compared with resting segments; ‡ P ⬍ 0.05 compared with resting and dipyridamole-treated segments;
§P ⬍ 0.05 compared with 20 ␮g 䡠 kg⫺1 䡠 min⫺1 dobutamine-treated segments.
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.2 on May 12, 2017
In the study dogs, after baseline data were obtained at
rest, pharmacological stress was induced with dipyridamole
(0.56 mg/kg, DuPont Pharmaceutical) administered intravenously over 4 min. Dipyridamole was selected instead of
adenosine because of its lower propensity to cause severe
hypotension in anesthetized dogs. Its coronary vasodilatory
effects are similar to that of adenosine (29). Data acquisition
was initiated 5 min later and completed in 15 min. One hour
later, dobutamine (Abbott Laboratories) was infused intravenously at an initial dose of 5 ␮g 䡠 kg⫺1 䡠 min⫺1 and increased
at 4-min intervals to 10, 20, and 30 ␮g 䡠 kg⫺1 䡠 min⫺1. If the
heart rate was not sufficiently elevated at 30 ␮g 䡠 kg⫺1 䡠 min⫺1
(⬍140 beats/min), then the dose was increased to 40
␮g 䡠 kg⫺1 䡠 min⫺1. Atropine was not used to increase the heart
rate even if it was ⬍140 beats/min at the peak dobutamine
dose. Although %WT data were acquired at each dose of
dobutamine, radiolabeled microspheres were injected only
during the peak dose, which was continued until all data
were obtained.
The dogs were euthanized with an overdose of pentobarbital sodium and KCl. Needles were inserted through the
heart at the levels of ultrasound transducer placement, and
the heart was excised and sliced at these levels for postmortem tissue analysis. Before analysis of MBF, the slices were
immersed in a solution of 1.3% 2,3,5-triphenyl tetrazolium
chloride (Sigma) and 0.2 M Sörensen’s buffer (KH2PO4 and
K2HPO4 in distilled water, pH 7.4) at 37°C for 20 min. With
the use of this method, areas of viable myocardium stain
brick red, whereas infarcted areas do not take up the stain
(3).
Statistical analysis. Data are expressed as means ⫾ SD.
Comparisons among more than two stages were made using
repeated measures ANOVA, whereas those between two
stages were performed using the Tukey test. For comparing
ratios, data were log transformed, and geometric means were
compared. Flow-function relations were fit to exponential
functions. Other relations were tested using least-squares fit
linear regression analysis. Differences were considered significant at P ⬍ 0.05 (2-tailed).
REGIONAL FLOW-FUNCTION RELATIONS IN CHRONIC CORONARY STENOSIS
H3061
Table 2. MBF data based on normal or reduced %WT
%WT
Variable
Resting transmural MBF,
ml 䡠 g⫺1 䡠 min⫺1
Resting endocardial MBF,
ml 䡠 g⫺1 䡠 min⫺1
Transmural MBF reserve,
ml 䡠 g⫺1 䡠 min⫺1
Endocardial MBF reserve,
ml 䡠 g⫺1 䡠 min⫺1
Normal (n ⫽ 42)
Reduced (n ⫽ 40)
1.0 ⫾ 0.3
1.0 ⫾ 0.2
1.0 ⫾ 0.4
1.1 ⫾ 0.3
3.9 ⫾ 1.2
2.2 ⫾ 0.9*
3.0 ⫾ 1.0
1.5 ⫾ 0.5*
Values are means ⫾ SD. MBF, myocardial blood flow. * P ⬍
0.0001.
Fig. 1. Relation between percent wall thickening (%WT) at rest
(x-axis) versus transmural myocardial blood flow (MBF) reserve
(y-axis). See text for details. The number of observations for the first
5 stages is 19 and the last stage is 17.
(abnormal response). The decrease in %WT with dobutamine was significantly greater (14 ⫾ 7 vs. 20 ⫾
5%, P ⫽ 0.03) in the 5 segments with an endocardial
MBF reserve of ⬍2 compared with the 18 segments
with a reserve of 2–3 (n ⫽ 18).
Only 6 of 42 segments with normal function at rest
demonstrated reduced %WT after dipyridamole infusion. The endocardial MBF reserve in these segments
(2.7 ⫾ 0.8) was no different from the remaining 36
segments that exhibited normal %WT (3.1 ⫾ 1.1, P ⫽
0.42).
DISCUSSION
Unlike the acute experimental setting, where reduction in regional %WT occurs only when MBF is reduced
(5, 30), resting %WT and MBF may not be related in
the setting of chronic coronary stenoses (2, 24, 29). A
new finding of our study is that, in the presence of
chronic noncritical coronary stenosis without collateral
development or infarction, the degree of resting %WT
is related to MBF reserve. Similarly, the %WT response during dobutamine is also related to MBF reserve. These findings lend further insight into the
complex pathophysiology of chronic coronary stenoses
Fig. 3. Relation between dobutamine dose (x-axis) and %WT (y-axis)
for myocardial segments with varying degrees of endocardial MBF
reserve. F, Œ, and ƒ, endocardial MBF reserves of ⬎3, 2–3, and ⫾ 1
SD. See text for details.
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.2 on May 12, 2017
in all segments. Transmural MBF reserve measured
during dipyridamole, however, was reduced (⬍3) in
segments with reduced %WT at rest (Fig. 1). The reduction in MBF reserve was even greater in the endocardium (Fig. 2). Reduced resting %WT was associated
with endocardial MBF reserve of ⬍2. A close coupling
between resting %WT and both transmural as well as
endocardial MBF reserve was noted (r ⫽ 0.81 and r ⫽
0.85, respectively, P ⬍ 0.0001).
Whereas the mean %WT did not change with dipyridamole, all segments demonstrated a progressive increase in %WT with incremental doses of dobutamine
up to a dose of 20 ␮g 䡠 kg⫺1 䡠 min⫺1 (Table 1). The mean
%WT was less at 40 compared with 20 ␮g 䡠 kg⫺1 䡠 min⫺1
(biphasic response). Segments that demonstrated normal %WT at rest had a significantly greater augmentation of %WT for each dose of dobutamine compared
with those that showed reduced % WT (Table 1).
Figure 3 illustrates the relation between dobutamine
dose and %WT for all myocardial segments. Irrespective of the endocardial MBF reserve, all segments
showed increased %WT with dobutamine up to a dose
of 20 ␮g 䡠 kg⫺1 䡠 min⫺1. %WT above this dose, however,
was influenced by the endocardial MBF reserve. All 19
segments with a reserve of ⬎3 showed continued increases in %WT up to the peak dobutamine dose (normal response), whereas the 23 segments with a reserve
of ⬍3 demonstrated a decreases in %WT when the dose
of dobutamine was increased above 20 ␮g 䡠 kg⫺1 䡠 min⫺1
Fig. 2. Relation between %WT at rest (x-axis) versus endocardial
MBF reserve (y-axis). See text for details. The number of observations for MBF reserve of ⬎2 is 18 for the first 5 stages and 16 for the
last stage. The number of observations for MBF reserve of ⬍2 is 5 in
all stages.
H3062
REGIONAL FLOW-FUNCTION RELATIONS IN CHRONIC CORONARY STENOSIS
ischemia appears to be the underlying mechanism of
inducible reduction in %WT. Our results from this
chronic stenosis model indicate that the individual
response of each segment to dobutamine is influenced
by the endocardial MBF reserve in that segment. If
this reserve is ⬎3, %WT will show a normal response
even at the maximal dose of dobutamine. In comparison, endocardial MBF reserve of ⱕ3 results in reduced
%WT, the severity of which depends on the magnitude
of impairment in MBF reserve. When MBF reserve is
abnormal, the response to dobutamine is biphasic, with
%WT increasing at low to moderate doses of dobutamine only to worsen at higher doses. This biphasic
response has been shown to correlate with the presence
of severe coronary stenoses in the clinical setting (22).
Dobutamine has also been used to determine myocardial viability in patients with reduced %WT at rest
(1, 19, 22). Although experimental studies have elucidated the mechanisms by which viability can be assessed with the use of dobutamine echocardiography
after acute myocardial infarction (17, 25, 26), there are
no experimental data indicating the basis for its use in
the assessment of viability in the setting of chronic
coronary stenoses, where collateral flow is not yet established. Our results indicate that when reduced resting %WT is seen in the presence of normal resting MBF
and the absence of infarction, increasing the dose of
dobutamine results in improvement of %WT before
worsening occurs: the biphasic response (1). This response likely occurs from demand ischemia and also
supports stunning as the basis of the underlying
chronic dysfunction. The reason this response has been
associated with recovery of regional function after revascularization (1) is likely related to the amelioration
of demand ischemia and recurrent stunning after the
procedure.
As would be expected, we did not see any significant
change in mean %WT with dipyridamole. Only six
segments showed inducible reduction in %WT with
this drug, and these segments did not have a significantly lower MBF reserve compared with those that
exhibited normal %WT. In this regard, our results are
similar to those obtained in an acute open-chest canine
model (4). Dipyridamole may occasionally cause demand ischemia because of reflex tachycardia resulting
from its mild hypotensive effect. Supply ischemia may
also occur with this drug due to the “steal” phenomenon (8), which is more likely to occur in the presence of
severe stenosis and abundant collateral development.
In our model, collateral vessels develop later (2) and so
could not have affected the myocardial response to
dipyridamole.
Study limitations. In our model of multivessel stenosis, it was difficult to judge which coronary artery
would become critically narrowed first. It is also possible that the stenosis on both arteries could progress
simultaneously. However, the stenosis on the LAD
coronary artery was always placed distal to the origin
of the first septal perforator. The septal region at the
upper papillary muscle level, therefore, always demonstrated normal transmural MBF reserve (⬎3) and nor-
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.2 on May 12, 2017
as well as the mechanisms underlying the detection of
coronary stenosis and myocardial viability using pharmacological stress in this setting.
%WT at rest. A close coupling between regional MBF
and %WT has been demonstrated in studies where
MBF is acutely altered, with %WT decreasing in concert with the decline in resting MBF (5, 30). Additionally, reduction in %WT has also been demonstrated
after myocardial infarction (6, 14). Thus, in the clinical
setting, resting reduction in %WT is generally thought
to represent either a reduction in resting MBF (unstable angina or hibernating myocardium) or a prior myocardial infarction. Although reduced %WT has been
reported during rest despite normal resting MBF in
both canine models as well as in humans with chronic
coronary stenoses (2, 24, 29), the normal resting MBF
has been attributed to collateral development. It has
been postulated that, in the presence of a noncritical
stenosis that does not reduce resting MBF (⬍85% luminal diameter narrowing), intermittent demand ischemia results in myocardial “stunning” (1, 24, 29).
Whether the same pathophysiology is operative in the
absence of collateral flow is not known.
A new finding of our study is that, in the presence of
a noncritical coronary stenosis before the development
of substantial collaterals, the severity of abnormal
%WT is closely related to the degree of impairment in
MBF reserve. Because endocardial thickening is the
major determinant of %WT (5, 18, 30), the relation
between endocardial MBF reserve and %WT is particularly intriguing. It is likely that increases in myocardial oxygen demand from the activities of daily living
result in repeated episodes of demand ischemia in the
endocardium with little time for recovery, producing a
perpetual state of myocardial dysfunction. It has been
previously shown, in chronically instrumented dogs,
that even the sight of food can increase coronary blood
flow by 40% (15). Thus unlike humans, who may not
increase their myocardial oxygen demand substantially at rest, sedentary dogs apparently do.
Whereas myocardial stunning has been described
largely in the setting of transient reductions in MBF,
“supply ischemia,” persistent myocardial dysfunction,
has also been reported after episodes of demand ischemia (11–13). Although we have no direct measurements of myocardial oxygen demand, the finding of
reduced endocardial MBF reserve provides strong support for myocardial stunning. The relation between
%WT at rest and the degree of reduction in MBF could
be explained by ischemia occurring not only earlier
with a more severe stenosis but also lasting longer.
%WT in response to pharmacological stress. Our results also demonstrate the mechanisms of the myocardial response to dobutamine in the setting of chronic
coronary stenoses. Although dobutamine echocardiography is routinely used in clinical practice for the
detection of chronic coronary stenoses (9, 22), there is a
surprising paucity of data elucidating the mechanism
by which %WT is reduced distal to a stenosis. The only
data available are from an acute model of graded stenoses (16), where, as implied in our study, demand
REGIONAL FLOW-FUNCTION RELATIONS IN CHRONIC CORONARY STENOSIS
DuPont Pharmaceuticals, North Billerica, Massachusetts, provided the radiolabeled microspheres. Advanced Technology Laboratories, Bothell, Washington, provided the ultrasound system.
This study was supported in part by National Heart, Lung, and
Blood Institute Grant R01-HL-48890. K. Wei is the recipient of a
Mentored Clinical Scientist Development Award (K08-HL-03909)
from the National Institutes of Health. R. A. Pelberg was supported
by a training grant from the American Heart Association, Virginia
Affiliate, Glen Allen, Virginia, and M. Coggins was the recipient of a
medical student research grant from the American Diabetes Association, Washington, DC.
These data were presented in part at the 71st Annual Scientific
Session of the American Heart Association in Dallas, Texas, and in
part at the 48th Annual Scientific Session of the American College of
Cardiology in New Orleans, Louisiana.
REFERENCES
1. Afridi I, Kleiman NS, Raizner AE, and Zoghbi WA. Dobutamine echocardiography in myocardial hibernation: optimal dose
and accuracy in predicting recovery of ventricular function after
coronary angioplasty. Circulation 91: 663–670, 1995.
2. Firoozan S, Wei K, Linka A, Skyba DM, Goodman NC, and
Kaul S. A canine model of chronic ischemic cardiomyopathy:
characterization of regional flow-funtion relations. Am J Physiol
Heart Circ Physiol 276: H446–H455, 1999.
3. Fishbein MC, Meerbaum S, Rit J, Lando U, Kanmatsuse K,
Mercier JC, Corday E, and Ganz W. Early phase acute
myocardial infarct size quantification: validation of the triphenyl
tetrazolium chloride tissue enzyme staining technique. Am
Heart J 101: 593- 600, 1981.
4. Fung AY, Gallagher KP, and Buda AJ. The physiologic basis
of dobutamine as compared with dipyridamole stress interventions in the assessment of critical coronary stenosis. Circulation
76: 943–951, 1987.
5. Gallagher KP, Matsuzaki M, Koziol JA, Kemper WS, and
Ross JJ Jr. Regional myocardial perfusion and wall thickening
during ischemia in conscious dogs. Am J Physiol Heart Circ
Physiol 247: H727–H738, 1984.
6. Gibbons EF, Hogan RD, Franklin TD, Nolting M, and
Weyman AE. The natural history of regional dysfunction in a
canine preparation of chronic infarction. Circulation 71: 394–
402, 1985.
7. Gould KL. Pressure-flow characteristics of coronary stenoses in
unsedated dogs at rest and during coronary vasodilation. Circ
Res 43: 245-252, 1978.
8. Gross GJ and Warltier DC. Coronary steal in four models of
single or multiple vessel obstruction in dogs. Am J Cardiol 48:
84–92, 1981.
9. Hays JT, Mahmarian JJ, Cochran AJ, and Verani MS.
Dobutamine thallium-201 tomography for evaluating patient
with suspected coronary artery disease unable to undergo exercise or vasodilator pharmacologic stress testing. Am J Cardiol
21: 1583–1590, 1993.
10. Heyman MA, Payne BD, Hoffman JI, and Rudolf AM. Blood
flow measurements with radionuclide-labeled. Prog Cardiovasc
Dis 20: 52–79, 1977.
11. Homans DC, Sublett E, Dai XZ, and Bache RJ. Persistence
of regional left ventricular dysfunction after exercise-induced
myocardial ischemia. J Clin Invest 77: 66–73, 1986.
12. Kamada T, Gallagher KP, Shirato K, McKown D, Miller M,
Kemper WS, White F, and Ross J Jr. Reduction of exerciseinduced regional myocardial dysfunction by propranolol. Studies
in a canine model of chronic coronary artery stenosis. Circ Res
46: 190–200, 1980.
13. Kloner RA, Allen J, Cox TA, Zheng Y, and Ruiz CE. Stunned
left ventricular myocardium after exercise treadmill testing in
coronary artery disease. Am J Cardiol 68: 329–334, 1991.
14. Lieberman AN, Weiss JL, Jugdutt BI, Becker LC, Bulkley
BH, Garrison JG, Hutchins GM, Kallman CA, and Weisfeldt ML. Two-dimensional echocardiography and infarct size:
relationship of regional wall motion and thickening to the extent
of myocardial infarction in the dog. Circulation 63: 739–746,
1981.
15. Marchetti G, Merlo L, and Noseda V. Response of coronary
blood flow to some natural stresses of excitement in the conscious dog. Pflügers Arch 298: 200–212, 1968.
16. McGillem MJ, DeBoer SF, Friedman HZ, and Mancini
GBJ. The effects of dopamine and dobutamine on regional function in the presence of rigid coronary stenoses and subcritical
impairments of reactive hyperemia. Am Heart J 115: 970–977,
1988.
17. Mercier JC, Lando U, Kanmatsuse K, Ninomiya K, Meerbaum S, Fishbein MC, Swan HJC, and Ganz W. Divergent
effects of inotropic stimulation on the ischemic and severely
depressed reperfused myocardium. Circulation 66: 397–400,
1982.
18. Myers JH, Stirling MC, Choy M, Buda AJ, and Gallagher
KP. Direct measurement of inner and outer wall thickening
dynamics with epicardial echocardiography. Circulation 74:
164–172, 1986.
19. Pierard LA, De Landsheere CM, Berthe C, Rigo P, and
Kulbertus HE. Identification of viable myocardium by echocardiography during dobutamine infusion in patients with myocardial infarction after thrombolytic therapy: comparison with
positron emission tomography. J Am Coll Cardiol 15: 1021–
1031, 1990.
20. Rossen JD, Quillen JE, Lopez AG, Stenberg RG, Talman
CL, and Winniford MD. Comparison of coronary vasodilation
with dipyridamole and adenosine. J Am Coll Cardiol 18: 485–
491, 1991.
21. Senior R, Kaul S, and Lahiri A. Myocardial viability on
echocardiography predicts long-term survival after revascularization in patients with ischemic congestive heart failure. J Am
Coll Cardiol 33: 1848–1854, 1999.
22. Senior R and Lahiri A. Enhanced detected of myocardial
ischemia by stress echocardiography utilizing the ‘biphasic’ response of wall thickening during low- and high-dose dobutamine
infusion. J Am Coll Cardiol 26: 26–32, 1995.
23. Schowski RA, Yvorchuk KJ, Yang Y, Rattes MF, and Chan
KL. Dobutamine and dipyridamole stress echocardiography in
patients with a low incidence of severe coronary artery disease.
J Am Soc Echocardiogr 8: 482–487, 1995.
24. Shen YT and Vatner SF. Mechanism of impaired myocardial
function during progressive coronary stenosis in conscious pigs.
Hibernation versus stunning? Circ Res 76: 479–488, 1995.
25. Sklenar J, Camarano G, Goodman NC, Ismail S, Jayaweera AR, and Kaul S. Contractile versus microvascular reserve
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.2 on May 12, 2017
mal %WT (⬎30%) and consequently was used as the
control bed. In the normal heart, MBF reserve is similar in all beds (7). Monitoring of myocardial oxygen
tissue levels during daily activities of these animals
could have provided more precise insights into the
mechanism of myocardial dysfunction. The exact
mechanism underlying the close relation between
%WT at rest and the impairment of the MBF reserve
also remains unclear and requires further study.
In conclusion, we have described quantitative flowfunction relations in the setting of noncritical chronic
coronary stenoses before the development of substantial collaterals and in the absence of infarction. We
elucidated the putative mechanism of inducible decreases in %WT and the basis for detecting myocardial
viability during dobutamine infusion in this setting.
We have shown that all these findings are different
manifestations of abnormal MBF reserve in the setting
of chronic coronary stenoses. These findings add further insights into the complex pathophysiology of
chronic coronary artery stenoses.
H3063
H3064
REGIONAL FLOW-FUNCTION RELATIONS IN CHRONIC CORONARY STENOSIS
for the determination of the extent of myocardial salvage after
reperfusion: the effect of residual stenosis. Circulation 94: 1430–
1440, 1996.
26. Sklenar J, Ismail S, Villanueva FS, Goodman NC,
Glasheen WP, and Kaul S. Dobutamine echocardiography
for determining the extent of myocardial salvage after reperfusion: an experimental evaluation. Circulation 90: 1503–1512,
1994.
27. Sklenar J, Jayaweera AR, and Kaul S. A computer-aided
approach for the quantification of regional left ventricular function using two-dimensional echocardiography. J Am Soc Echocardiogr 5: 33–40, 1992.
28. Sonnenblick EH, Frishman WH, and LeJemtel THT. Dobutamine. A new synthetic cardioactive sympathetic amine.
N Engl J Med 300: 17–22, 1979.
29. Vanoverschelde JJ, Wijns W, Depre C, Essamri B, Heyndrickx GR, Borgers M, Bol A, and Melin JA. Mechanism of
chronic regional postischemic dysfunction in humans. New insights from the study of noninfarcted collateral-dependent myocardium. Circulation 87: 1513–1523, 1993.
30. Weintraub WS, Hattori S, Aggarwal JB, Bodenheimer MM,
Banka VS, and Helfant RH. The relationship between myocardial blood flow and contraction by myocardial layer in the canine
left ventricle during ischemia. Circ Res 48: 430–438, 1981.
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.2 on May 12, 2017