(Circulation. 1997;96:3992-4001.)
© 1997 American Heart Association, Inc.
Articles |
Nitroglycerin Enhances the Ability of Dobutamine Stress Echocardiography to Detect Hibernating Myocardium
From the Division of Cardiology, Hartford Hospital, University of Connecticut School of Medicine (Hartford).
Correspondence to Chunguang Chen, MD, Division of Cardiology, Hartford Hospital, 80 Seymour St, Hartford, CT 06102.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background A biphasic response of wall thickening with initial improvement and subsequent deterioration during dobutamine stress echocardiography (DSE) has been increasingly used for detection of hibernating myocardium. However, the improvement of wall thickening at low-dose DSE may be limited in hibernating myocardium by severe hypoperfusion. Nitroglycerin (NTG) improves myocardial perfusion, reduces oxygen demand, and may enhance low-dose dobutamine to improve wall thickening.
Methods and Results A pig model of myocardial hibernation of 24
hours to 7 days was created through severe left anterior descending
coronary artery stenosis with coronary flow
reductions of 
40%, producing severe regional left
ventricular dysfunction but no infarction in seven pigs.
Myocardial infarction was produced in five pigs with occlusion of the
artery. DSE was performed with incremental doses with and without an
NTG infusion of 50 to 100 µg/min. In the hibernating group, NTG alone
improved wall thickening in the hibernating region modestly from
11.4±7.2% at baseline to 19.1±7.0%. The improvement was associated
with increased regional coronary flow from 0.46±0.12 to
0.55±0.13 mL · beat-1 · 100 g
myocardium-1 (P<.05). There
was an additive effect of NTG to low-dose (2.5 to 5 µg ·
kg-1 · min-1) dobutamine
on wall thickening in the hibernating region. The improvement of wall
thickening of hibernating myocardium with NTG and
dobutamine, from 23.7±11.1% to 31.1±8.9%
(P<.001), was associated with an increase in regional
coronary flow (P<.01). NTG did not prevent high
doses of dobutamine from inducing deterioration of wall
thickening in hibernating myocardium. In the infarcted
group, no improvement in wall thickening was observed in infarcted
regions during NTG infusion, dobutamine infusion, or the
combination.
Conclusions NTG enhances the improvement of wall thickening at low-dose dobutamine and does not prevent high-dose dobutamine from inducing ischemia in hibernating myocardium. Thus, NTG augments the biphasic response of wall thickening and improves the accuracy of DSE for detecting viable myocardium.
Key Words: coronary disease ischemia • stunning • echocardiography • nitroglycerin
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Dobutamine stress echocardiography is used as a diagnostic tool to noninvasively detect coronary artery stenoses and differentiate viable from infarcted myocardium in patients with LV dysfunction.1–6 It has been demonstrated that incremental doses of dobutamine characteristically induce a biphasic response with an improvement in wall thickening initially at low doses and deterioration subsequently at high doses in LV regions with hibernating myocardium subtending a critical coronary stenosis.7–9 However, this characteristic biphasic pattern was observed in only 60% to 76% of hibernating myocardial regions with low-flow perfusion with severe coronary artery stenosis in both human9 and animal7 studies.
In a pig model of short-term myocardial hibernation subtending a severe coronary stenosis, the degree of the initial improvement in wall thickening with dobutamine has been shown to correlate with an increase in regional coronary flow.7 Therefore, the failure of dobutamine to improve regional wall thickening may result from severely reduced perfusion that does not improve adequately with low-dose dobutamine. We hypothesized that agents that improve coronary flow and the oxygen supply/demand balance may enhance the sensitivity of dobutamine stress echocardiography for detection of hibernating myocardium. Nitroglycerin can improve the oxygen supply-to-demand ratio by increasing coronary flow in hypoperfused regions with severe coronary stenosis,10 redistributing flow favorably to the subendocardium,11–13 and by decreasing ventricular preload and afterload through reduction in venous blood return to the heart.14 Thus, nitroglycerin may magnify the initial improvement of wall thickening by low doses of dobutamine and enhance the sensitivity of detecting hibernating myocardium with the use of dobutamine stress echocardiography. However, whether nitroglycerin protects hibernating myocardium against ischemia with a deterioration of wall thickening at high doses of dobutamine is not known. Accordingly, this study was designed to test these hypotheses in a pig model of myocardial hibernation: Specific questions that we addressed were (1) whether nitroglycerin can improve myocardial perfusion in regions supplied by a severe coronary stenosis and enhance wall thickening of hibernating myocardium; (2) whether dobutamine and nitroglycerin have additive effects to increase wall thickening in hibernating myocardium; and (3) whether nitroglycerin can protect against the deterioration of wall thickening at high doses of dobutamine, altering the biphasic response of wall thickening to incremental doses of dobutamine in hibernating myocardium.
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Methods |
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Seven pigs weighing 45.7±7.3 kg were studied. The study protocol was approved by the Committee on Animal Care at Hartford Hospital, and the animal care guidelines of the American Heart Association were followed. A pig model of 24-hour to 7-day myocardial hibernation in regions subtending severe LAD stenosis was created and has been previously described.15 Briefly, general anesthesia was applied with isoflurane (0.5% to 1.5%) and a 40% oxygen/60% nitrous oxide mixture. A midline thoracotomy was performed, and the heart was suspended in a pericardial cradle. A 3F coronary perfusion catheter was introduced retrograde via the coronary sinus to the cardiac vein parallel to the stenotic LAD segment for monitoring oxygen content, lactate, and pH. Full anticoagulation was achieved and maintained with 200 IU/kg heparin IV, followed by 30 IU/kg per hour. The proximal LAD was dissected free over 1 to 2 cm to accept a coronary flowmeter probe (Transonic) for measuring of LAD flow.
To produce myocardial hibernation, a LAD stenosis was created
by gradually filling the hydraulic occluder with saline (n=2) or by the
use of a silk tie (n=5) to partially occlude the LAD to reduce resting
LAD flow to 60% of baseline.15 The
stenosis was maintained for 24 hours (n=2) or 7 days (n=5) to
produce myocardial hibernation of different durations because
myocardial hibernation of different durations may have different
features.16,17
To produce myocardial infarction, in another five pigs, the LAD was totally occluded for 15 to 25 minutes, and a LAD stenosis was created as described above to reduce coronary flow by 30% to 40%. The residual stenosis was maintained for 24 hours in two pigs and 7 days in three pigs.
Experimental Protocol
Baseline measurements of heart rate, aortic pressure, left
atrial pressure and regional coronary flow, coronary
venous lactate, pH, and oxygen content were obtained under stable
conditions, defined as two consecutive measurements at 5-minute
intervals with a difference in pH of 
0.02, coronary flow of
3 mL, and mean blood pressure of 5 mm Hg.
In the hibernating group of seven pigs, dobutamine stress echocardiography was first performed with incremental doses of dobutamine infusion from 2.5, 5, 10, and 20 to 30 µg · kg-1 · min-1 at 3-minute intervals. The dobutamine stress test was terminated if a significant regional wall motion abnormality was noted through online visual evaluation. After normalization from the previous stages for 15 to 20 minutes, a nitroglycerin infusion was started with the dose titrated to reduce systolic blood pressure by 5 to 10 mm Hg or to increase heart rate by 5 to 10 bpm. The nitroglycerin dose ranged from 50 to 100 µg/min. After recording of hemodynamic and echocardiographic changes with nitroglycerin, the same dobutamine stress protocol was repeated with simultaneous nitroglycerin infusion. Measurements of coronary flow, heart rate, blood pressure, and left atrial pressure were obtained at the end of each experimental stage. Coronary venous blood samples were obtained at low doses of dobutamine when the improvement of regional wall thickening in the hibernating region was maximal and at the maximal dose of dobutamine.
In the infarcted group of five pigs, nitroglycerin infusion was initiated first and followed by a dobutamine stress protocol as outlined above. After 30 minutes of normalization from the previous stages, the dobutamine stress protocol was repeated without nitroglycerin.
Echocardiography Measurements
Two-dimensional epicardial echocardiography
was performed at the short-axis view at midpapillary muscle level of
the LV. Images were obtained from the epicardial surface of the right
ventricle and recorded on a videotape for offline analysis
of wall thickening. The end-diastolic frame of the
echocardiographic images was selected using the onset
of the Q wave of the ECG; the frame with the smallest left
ventricular cavity was defined as end systole. The
endocardial and epicardial borders of each frame were manually traced
according to the technique recommended by the American Society of
Echocardiography with a cursor and digitizing
trackball that were directly interactive with
echocardiographic images on a commercially available
computer system (Nova Microsonics). The papillary muscles were
excluded. Premature beats and the first beat after an extrasystole were
excluded. The tracings were digitized and stored. The LV was divided
into 100 equal chords, and regional wall thickening was quantified
according to a centerline method,8,18 as shown in
Fig 1
. The left ventricle was then
divided into eight equal segments, starting from the conjunction of the
LV inferior wall and the right ventricular or
inferior ventricular septum, midseptum,
anterior septum, anterior wall, anterolateral wall, posterolateral
wall, posterior wall, and inferior wall.
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In the hibernating group, the anterior septum and anterior wall were considered the regions supplied by LAD. Although LAD also supplied the anterolateral wall, this segment was not included in the analysis for wall thickening in the LAD region because of the possibility of overlapping perfusion to this segment from the circumflex artery and the LAD. The inferior wall was considered the normal control region. Wall thickening from 12 chords in each region was averaged for comparisons.
In the infarcted group, the anatomic infarcted location on TTC staining was defined through the use of natural markers of the LV such as distance from the junction between interventricular septum and the anterior wall and the lateral papillary muscles. The infarction was typically located centrally in the area at risk (LAD regions). The infarcted zone involved approximately one third of the area at risk (see "Results") in the infarcted group in this study. A total of 36 chords were assigned to the LAD region, including anterior septum, anterior wall, and anterolateral wall. Therefore, the central third of the total regions supplied by the LAD or 12 chords in the center of the LAD region were defined as infarcted zone. In visual assessment, the corresponding infarcted center usually presented the most severe wall thickening abnormalities when the echocardiographically defined infarcted center was aligned to the pathologically confirmed infarcted center through the use of natural anatomic markers such as papillary muscles and the junction of interventricular septum and anterior wall. The adjacent 12 chords (6 chords on each side) of wall thickening to the infarcted zone were considered to be the peripheral viable (hibernating/stunned) region around the infarction, which was supplied by the stenotic LAD. To avoid the tethering effect of wall motion from adjacent normal regions, the most peripheral 12 chords in the LAD regions (the area at risk) that were adjacent to the midseptum and lateral wall were excluded in the analysis of wall thickening.
All echocardiographic measurements were performed by two observers who were blinded to each other's results. Their results were averaged. Interobserver and intraobserver variabilities of measurement of regional wall thickening in our laboratory have been reported previously.8 The LV end-diastolic and -systolic volumes were determined according to a two-dimensional echocardiographic area-length method in which the area was measured from LV cross section at papillary muscle level and length was obtained from a long-axis view.19
Regional Myocardial Blood Flow Measurements
Regional myocardial blood flow was measured with a cuff
flow probe connected to a Transonic flowmeter. At the conclusion of
each experiment, the flowmeter was calibrated against a known rate of
blood flow to ensure the accuracy of the measurements. After completion
of the experiment, the pigs were killed, and methylene blue was
injected into the LAD to stain the myocardium supplied by
the stenotic vessel. The stained tissue was dissected and
weighed to determine the regional myocardial mass perfused by the
stenotic LAD. Regional coronary blood flow was
expressed as mL · min-1 · g of wet
tissue-1.8
Regional Myocardial Metabolic Measurements
To inhibit glycolysis, arterial and
coronary venous blood samples were obtained
anaerobically in cold, dry syringes containing heparin
fluoride. Samples were divided for blood gases and lactate
analysis, stored in ice, and processed immediately after the
experiment. Blood gases were analyzed in duplicate, and the
values were averaged. Plasma for lactate content was deproteinated with
perchloric acid, neutralized with potassium hydroxide and imidazole
buffer, and then analyzed according to the enzymatic method.
Regional myocardial oxygen consumption was calculated by subtracting
the coronary venous oxygen content from the
arterial oxygen content and then multiplying the regional
transmural blood flow supplied by the LAD. Lactate
consumption/production was calculated by subtracting the
coronary venous lactate from arterial lactate and
then multiplying the regional transmural blood flow.
Pathological and Histological Examinations
At the conclusion of the experiment, the pigs were killed with
an overdose of isoflurane, and the heart was arrested with an
intravenous injection of 10 mL of 10% KCl. Methylene blue
was injected distally into the stenotic LAD to delineate the
area at risk as described previously. The LV was cut into cross
sections at 0.5-cm intervals from apex to base. The area at risk was
dissected and weighed. The LV sections (both the normal portion and the
area at risk) were stained with 1.0% TTC to identify gross myocardial
necrosis.7,15 In pigs with infarction (necrosis,
not stained by TTC), total surface area at risk and necrotic area were
traced onto transparent paper. The infarcted size for each pig was
calculated by integrating necrotic areas and normal areas from all LV
sections. All LV sections, including area with infarction, were then
fixed with 10% formalin for 
48 hours, embedded in paraffin, sliced
into 5-µm sections, and stained with hematoxylin and eosin and
Mason's trichrome for light microscopic examinations.
Statistical Analysis
All parameters were expressed as mean±SD.
Repeated-measures ANOVA was used for parametric data to examine
the difference between stages. Least-squares linear regression was
applied to test the correlation between two parameters.
Fisher's exact test was used to examine nonparametric
data. A value of P<.05 was considered statistically
significant.
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Results |
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In seven pigs, no myocardial infarction was detected by TTC; these seven pigs were included in the hibernating group (Table 1
).
Microscopic examination showed several areas of minimal (0.5 to 2
mm) patchy replacement fibrosis with granular tissue consistent
with myocardial necrosis in the subendomyocardium in two
pigs with 7 days of LAD stenosis. LAD coronary flow was
reduced from 1.00±0.14 mL · g-1 ·
min-1 at baseline to 0.58±0.20 mL ·
g-1 · min-1 after
creation of the stenosis or from 0.86±0.16 mL ·
g-1 · min-1 at
baseline to 0.46±0.12 mL · 100 g-1
· beat-1 with the stenosis after
correction for heart rate. Wall thickening in regions (anterior and
anteroseptal) supplied by the stenotic artery was reduced from
38.4±4.0% to 11.7±7.2% (P<.001). Mean blood pressure
was not different before and after the LAD stenosis.
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In five pigs, myocardial infarction was detected with TTC,
confirmed with microscopic examination, and included in the infarcted
group. Mean infarcted area was 26.7±6.4% of the area at risk (LAD
regions including anterior septum, anterior wall, and anterolateral
wall). The infarction was transmural in three pigs as defined by
infarcted area involving >50% of LV wall thickness. In two pigs, the
infarction was located only in the subendomyocardium. In
the infarcted group, LAD flow was reduced from 1.06±0.13 to 0 during
the temporal total occlusion of the LAD for 15 to 25 minutes. After
release of the occlusion and placement of the LAD stenosis, LAD
flow was 0.67±0.19 mL · g-1 ·
min-1 in this group (Table 2). Regional wall thickening was reduced
from 38.6±4.5% to -0.8±2.5%. Other parameters are
included in Table 2.
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Effects of Nitroglycerin and Dobutamine
on Hibernating Myocardium
Baseline
Table 2
shows that coronary
flow increased significantly from 0.58±0.20 mL ·
g-1 · min-1 at the
stenosis baseline to 0.69±0.20 mL ·
g-1 · min-1 after
infusion of nitroglycerin (P<.01);
similarly, coronary flow per beat increased from 0.46±0.12 to
0.55±0.13 mL · 100 g-1 ·
beat-1 (P<.05), a 20% increase on
average, whereas LV end-diastolic volume and left atrial
pressure decreased after nitroglycerin
(P<.01 and <.05, respectively). Wall thickening in the LAD
region improved from 11.4±7.2% before nitroglycerin
to 19.1±7.0% after nitroglycerin (P<.01,
Figs 1, 2, and 3), and an improvement of wall thickening
of 7%, which was beyond the intraobserver
variability,8 was observed in three of seven
pigs. In contrast, the improvement of wall thickening in the control
(inferior) region was not statistically significant
(40.2±6.0% before and 43.1±4.1% after
nitroglycerin, P>.05). Heart rate increased
slightly (P<.05). Mean aortic pressure tended to decrease
with nitroglycerin, but the difference was not
statistically significant.
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Effects of Nitroglycerin During
Dobutamine Stress (Table 1)
Additive Effect of Nitroglycerin and
Dobutamine at Low Doses. The dose used for the maximal
improvement of wall thickening (stages of low-dose
dobutamine) was 2.86±0.94 µg ·
kg-1 · min-1 with
nitroglycerin and 3.93±1.34 µg ·
kg-1 · min-1
without nitroglycerin. The heart rate was higher at
dobutamine doses of 10 and 20 µg ·
kg-1 · min-1 with
nitroglycerin than without
nitroglycerin (Fig 3A). Rate-pressure
production, mean left atrial pressure, and
end-diastolic volume tended to be lower with
nitroglycerin than without for the same dose of
dobutamine, but the differences did not reach statistical
significance. With low-dose dobutamine, coronary
flow per beat was 0.49±0.14 with dobutamine alone but
0.60±0.14 mL · 100 g-1 ·
beat-1 (P<.01) with
nitroglycerin and dobutamine (Fig 3B).
Coronary flow increased from 0.55±0.13 with
nitroglycerin alone to 0.60±0.14 mL · 100
g-1 · beat-1, a
9% increase on average, with the combination of
nitroglycerin and dobutamine
(P<.05, Fig 3B).
Anterior wall thickening improved significantly with low-dose
dobutamine or nitroglycerin alone (Figs 2 and 3C). This improvement was more obvious with dobutamine
and nitroglycerin (31.1±8.9%) than with
dobutamine alone (23.7±11.1%, P<.01, Fig 3C).
The improvement of 7% in regional wall thickening was observed in
four of seven pigs with dobutamine alone and in all seven
pigs with the combination of nitroglycerin and
dobutamine. Inferior wall thickening did not
differ between stages with and without nitroglycerin
(56.0±2.6% and 51.8±6.4%, respectively, P=NS).
Effect of Nitroglycerin at High Doses of
Dobutamine. Heart rate with
nitroglycerin (180±25 bpm) was higher than without
(173±27 bpm, P<.05). Mean blood pressure was not
different. Coronary flow was higher with (0.77±0.24 mL
· g-1 · min-1)
than without (0.68±0.26 mL · g-1
· min-1 P<.01)
nitroglycerin at the maximal dobutamine
dose, as was coronary flow per beat (0.43±0.09 with versus
0.38±0.12 mL · 100 g-1 ·
beat-1 without nitroglycerin,
P<.05; Fig 3B). Wall thickening in the anterior region
deteriorated at both conditions compared with low-dose
dobutamine (each P<.001). At the maximal dose
of dobutamine, there was no difference in wall thickening
between stages with and without nitroglycerin
(5.6±4.9% with versus 7.1±5.2% without, P=NS; Fig 3C).
Wall thickening in the inferior regions was also similar
(63.2±4.9% with versus 63.9±4.0% without
nitroglycerin, P=NS). Left
ventricular end-diastolic volume was similar
with or without nitroglycerin (48.4±19.8 and
47.7±25.1 cm3, P>.05), as was
regional lactate production (P=NS).
The lowest dobutamine dose that produced the maximal
improvement of wall thickening was 2.5 µg ·
kg-1 · min-1 in
six of seven pigs and 5 µg · kg-1
· min-1 in one pig with
nitroglycerin, somewhat lower than the stage without
nitroglycerin (2.5 µg ·
kg-1 · min-1 in
three of seven pigs and 5 µg ·
kg-1 · min-1 in
four of seven pigs, P=NS). The maximal
dobutamine dose that induced the maximal deterioration of
wall thickening was 13±7 µg ·
kg-1 · min-1 with
nitroglycerin, slightly lower than the dose (19±11
µg · kg-1 ·
min-1) used without
nitroglycerin, but this did not reach statistical
significance (P=NS), probably because of the small number of
animals included. A maximal dose of 30 µg ·
kg-1 · min-1 was
used in four of seven pigs with dobutamine infusion only,
whereas no pig with the combination of dobutamine and
nitroglycerin received 30 µg ·
kg-1 · min-1. When
we compared regional wall thickening with and without
nitroglycerin (Fig 3) at each dose of
dobutamine (2.5, 5, 10, and 20 µg ·
kg-1 · min-1),
there was a significant difference between regional wall thickening
with and without nitroglycerin during
dobutamine infusion at some stages with the same dose. With
a low dobutamine dose of 2.5 µg ·
kg-1 · min-1, wall
thickening was significantly greater with nitroglycerin
than without nitroglycerin. With a high
dobutamine dose of 20 µg ·
kg-1 · min-1,
regional wall thickening was significantly lower with
nitroglycerin than without
nitroglycerin. There was no difference in wall
thickening with or without nitroglycerin at
intermediate dobutamine doses of 5 and 10 µg ·
kg-1 · min-1.
Factors Related to the Improvement of Regional Wall
Thickening
During low doses of dobutamine infusion with
nitroglycerin, regional coronary flow per beat
(r=.48, P<.05) and left ventricular
end-diastolic volume (r=.58, P<.01)
correlated with wall thickening in regions supplied by LAD. During high
doses of dobutamine with nitroglycerin,
regional coronary flow per beat (r=.60,
P<.01) and myocardial lactate production
(r=.64. P=.01) correlated significantly with the
deterioration of regional wall thickening in regions supplied by the
stenotic LAD. If data were pooled from low and high doses of
dobutamine with nitroglycerin, correlation
between the wall thickening and regional coronary flow per beat
was similarly significant (r=.53, P<.01; Fig 4).
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Effects of Nitroglycerin and Dobutamine
on Infarcted Myocardium and Viable Myocardium
Peripheral to the Infarction
Table 2 presents data illustrating the effects of
nitroglycerin with and without the addition of
dobutamine in the infarcted group. Although baseline LAD
coronary flow reduction was similar (P=NS) compared
with the hibernating group, regional wall thickening was more severely
reduced in the infarcted group than in the hibernating group. There was
no significant improvement of regional wall thickening in the infarcted
region either after nitroglycerin alone
(P=NS) or after the combination of
nitroglycerin and dobutamine
(P=NS). One pig (pig 88) with
subendomyocardial infarction involving
approximately one third of the wall thickness showed a significant
improvement (8%) in regional wall thickening with the
nitroglycerin and dobutamine combination.
In all pigs, wall thickening in the peripheral regions of
the infarction that was supplied by the stenotic LAD improved
significantly, from 3.6±2.0% at baseline to 6.6±2.1% with
nitroglycerin and to 16.4±5.8% with the combination
of nitroglycerin and dobutamine
(P<.05). The wall thickening in the peripheral
region of the infarction also improved from 3.6±2.0% to 11.3±6.2%
with low-dose dobutamine alone. Dobutamine
alone improved wall thickening of 8% in three of five pigs, and the
combination of nitroglycerin and dobutamine
improved wall thickening of 8% in all five pigs in the
peripheral regions of the infarction.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study demonstrates that nitroglycerin confers a limited improvement of wall thickening detectable by two-dimensional echocardiography in hibernating myocardium subtended by severe flow-limiting coronary stenoses. The addition of nitroglycerin to low-dose dobutamine further improves wall thickening in hibernating regions and enhances echocardiographic detection of recruitable contractile reserve in viable hibernating myocardium. This additive effect of nitroglycerin and dobutamine at low doses did not prevent high doses of dobutamine from inducing ischemia with deterioration of wall thickening in hibernating regions. Therefore, the addition of nitroglycerin to dobutamine stress testing augments the characteristic biphasic response of initial improvement and subsequent deterioration of hibernating myocardial wall thickening during incremental doses of dobutamine infusion. Because the biphasic response is being used to an increasing degree clinically as a marker of both viability and inducible ischemia in the regions with viable myocardium, these results imply that nitroglycerin may improve the sensitivity and accuracy of dobutamine stress echocardiography for the detection of viable, hibernating myocardium clinically.
Study Design Limitations and Advantages
A major limitation of this study was the use of a model with a
one-vessel (LAD) stenosis. This study ideally would have been
conducted in a model of myocardial hibernation with multivessel
coronary artery disease. Unfortunately, such a model has not
yet been successfully developed. The fact that
nitroglycerin can also improve coronary flow in
multivessel disease10,13,24–27 suggests the
possibility that results obtained in this study may be extrapolated to
multivessel coronary artery disease. Radioactive
microspheres were not applied to measure ratio of the
subendocardial and subepicardial myocardial blood flow distribution;
therefore, the effect of nitroglycerin on the
redistribution of myocardial blood flow in the hibernating region could
not be evaluated in this study.
Nitroglycerin was used intravenously in
this study. Whether sublingual nitroglycerin can be
used as a substitute was not evaluated; however, it is reasonable to
assume that similar hemodynamic and functional effects
can be achieved with sublingual nitroglycerin, although
an appropriate substitute dose needs to be determined. There is concern
that the protocol used in the hibernating group in which the
dobutamine stress test was performed first and the stress
test combining nitroglycerin and dobutamine
was performed second might have aided nitroglycerin in
inducing the improvement of wall thickening. However, baseline wall
thickening and coronary flow were similar at the first baseline
study before the dobutamine stress test only and the second
baseline study at 20 minutes after a full run of dobutamine
up to a maximal dose. This suggests that there was no significant
residual ischemia or postischemic hyperemia
(increase in coronary flow) after 20 minutes of
dobutamine stress test. This is further ensured by the
result of a similar enhancement in the LAD region of dysfunctional but
viable hibernating/stunned myocardium around the
infarcted regions in the infarcted group in which a different sequence
of tests was used: nitroglycerin infusion was first
used and followed by the combined dobutamine stress test,
30 minutes of normalization, and then dobutamine stress
test alone. Because intravenous
nitroglycerin has a half-time of 1 to 3 minutes,
residual effects of nitroglycerin may be minimal with
this protocol. This is supported by the fact that there were no
differences in baseline hemodynamic data,
coronary flow, and wall thickening before and after the first
run of nitroglycerin and dobutamine stress
test (Table 1).
Different durations (24 hours and 7 days) of myocardial hibernation may have different features and degrees of coronary flow and contractile reserves. Although this study included pigs with myocardial hibernation of 24 hours and 7 days, the limited number of animals studied prevents further analysis of the different effects of nitroglycerin or dobutamine on hibernating myocardium of different durations. Myocardial infarction defined as positive TTC staining may miss minimal microscopic myocardial necrosis, which can occur in patients with clinical unstable angina. Indeed, two of seven pigs had a mild degree of patchy replacement fibrosis with granular tissue, indicative of microscopic infarction. However, the vast majority of myocardium supplied by LAD was not infarcted in these two pigs; therefore, we attribute them to the hibernating group.
Although we can conclude that nitroglycerin does not protect high doses of dobutamine from inducing ischemia in hibernating myocardium subtending severe coronary stenosis, whether nitroglycerin potentiates high-dose dobutamine to induce ischemia is suggested but cannot be conclusively determined on the basis of this study. At a dobutamine dose of 20 µg · kg-1 · min-1, wall thickening was slightly more reduced by the addition of nitroglycerin to dobutamine protocol than by the use of dobutamine alone. This was associated with an increase in lactate production and a lower coronary venous pH at a dobutamine dose of 20 µg · kg-1 · min-1 compared with baseline. Unfortunately, no lactate or pH measurements were done at a dobutamine dose of 20 µg · kg-1 · min-1 for dobutamine infusion alone without nitroglycerin by study design where coronary venous blood was drawn at low-dose dobutamine when maximal improvement of wall thickening was observed by online visual estimation and at the maximal dose of dobutamine. The reduction in wall thickening of 20 µg · kg-1 · min-1 with nitroglycerin added to dobutamine was slightly less but statistically not different from the reduction in wall thickening at a dobutamine dose of 30 µg · kg-1 · min-1 without nitroglycerin. Unfortunately, by study design, the end point of termination of dobutamine infusion was defined by a clinically used protocol in which dobutamine infusion is terminated when there was deterioration of regional wall thickening by visual evaluation of wall thickening. According to this protocol, a maximal dobutamine dose of 30 µg · kg-1 · min-1 was used in four pigs without nitroglycerin, whereas no pigs had a maximal dobutamine dose of 30 µg · kg-1 · min-1 with the dobutamine-plus-nitroglycerin combination. Therefore, it is not known whether regional myocardial lactate production would have been higher and whether coronary venous pH would have been lower if a maximal dobutamine dose of 30 µg · kg-1 · min- 1 had been used with nitroglycerin.
Previous Studies
Angiographic studies in patients have demonstrated that
nitroglycerin improves regional ischemic
dysfunction and global LV ejection fraction, although the mechanism has
not been well elucidated.20–22 Improved regional
wall motion with nitroglycerin predicts recovery of LV
function after coronary artery bypass graft surgery. However,
because only a small number of patients have been included in these
angiographic studies with nitroglycerin, the exact
sensitivity, specificity, and predictive accuracy of
nitroglycerin are unknown. In a preliminary report by
Stadius et al,1,23 the sensitivity and accuracy
were 50% to 65% and 70 to 73% with angiography, respectively. With
echocardiography, the diagnostic value
of applying nitroglycerin to enhance wall thickening or
motion to predict functional recovery after
revascularization has not been systematically
studied.14
In myocardial perfusion imaging studies, nitroglycerin enhances myocardial blood flow during 201Tl reinjection and redistribution, and the combination of an isosorbide dinitrate infusion and rest 99mTc-sestamibi tomography increases tracer uptake in some chronically hypoperfused asynergic territories.24–27 The increased tracer uptake was associated with postrevascularization functional recovery.23 Therefore, nitroglycerin combined with nuclear perfusion studies at rest or during redistribution also appears promising for the noninvasive detection of viable hibernating myocardium.
Mechanism of the Effect of Nitroglycerin on
Regional Wall Thickening in Hibernating Myocardium
A significant correlation between improvement of wall thickening
and reduced LV end-diastolic volume with
nitroglycerin suggests that reduced wall stress may
contribute to increased wall thickening with
nitroglycerin. However, the correlation is only modest,
implying that other factors may be related. The improvement of
myocardial perfusion or coronary flow in regions with severe
coronary stenosis has been demonstrated by perfusion
imaging studies with 201Tl or sestamibi and by
regional coronary flow measurement using the
131Xe technique in
patients10 and by the microsphere
technique or Rb-86 clearance method in canine
studies.11,12 In this study, the observation that
the magnitude of improvement of coronary flow correlated
significantly with improved wall thickening supports the notion that
the two phenomena are related. Nitroglycerin improves
regional coronary flow, providing fuel for low-dose
dobutamine to enhance wall thickening. However, that
depressed wall thickening may not recover for days or weeks after
reperfusion of the hibernating myocardial
regions15 suggests that the increase in
coronary flow by nitroglycerin may not
proportionally improve wall thickening. Dobutamine enhances
hibernating myocardial contraction proportional to the increase in
coronary flow by nitroglycerin.
Nitroglycerin did not prevent hibernating myocardium subtending severe coronary stenosis from ischemia with deterioration of regional wall thickening at high doses of dobutamine infusion. This result contrasts with the observation that nitroglycerin protects against exercise and pacing-induced myocardial ischemia in regions with severe coronary stenoses.28–30 The explanation for this is only speculative. In patients with coronary stenoses, marked increases in LV diastolic pressure and LV volume are seen during exercise-induced ischemia, and the mechanism by which nitroglycerin protects against ischemia has been demonstrated to be a reduction in LV diastolic pressure and volume by nitroglycerin during exercise.26 In contrast, during dobutamine stress testing, in a normal ventricle without ischemia, LV end-diastolic volume and end-diastolic pressure decreased significantly at high doses of dobutamine infusion; even in ischemic LVs, end-diastolic volume did not change or decrease, and end-diastolic pressure increased only mildly at high doses of dobutamine in this study and in our previous studies in one-vessel coronary disease.7,8 Intracoronary dobutamine infusion in a pig model of short-term myocardial hibernation has been demonstrated to significantly decrease myocardial ATP and creatine phosphate content.31 Whether the addition of nitroglycerin with initially enhanced regional wall thickening accelerates the exhaustion of myocardial ATP and other high-energy compounds in the hibernating region, leading to deterioration of wall thickening in hibernating myocardium during dobutamine stress test, cannot be determined in this study. This study showed that there was a tendency toward an early deterioration of wall thickening during incremental doses of dobutamine infusion by the addition of nitroglycerin. However, the difference between maximal doses of dobutamine, which were used in this study with and without the addition of nitroglycerin, did not reach a statistical significance. Obviously, a large number of animals are required to conclusively determine whether nitroglycerin accelerates ischemia in the hibernating region during high doses of dobutamine infusion.
A biphasic response of wall thickening with initial improvement and subsequent deterioration was similarly observed in the peri-infarcted viable myocardial region supplied by a significant residual coronary stenosis, although myocardium in the peri-infarcted region may be stunned, hibernating, or both. The mechanism for the biphasic response in the stunned/hibernating region supplied by a significant coronary stenosis is likely similar in the hibernating myocardium. The deterioration of wall thickening of peri-infarcted myocardium supplied by a significant residual stenosis is most likely due to myocardial ischemia rather than a tethering effect from the dyskinetic infarcted region because at low-dose dobutamine, there was an initial improvement in wall thickening in the peri-infarcted viable myocardium, whereas wall thinning or dyskinetic wall motion already occurred in the infarcted center with necrotic myocardium. If the deterioration of wall thickening at high doses of dobutamine were due to the tethering effect, it would have developed at the initial low doses of dobutamine and there would not have been the initial improvement of wall thickening in peri-infarcted viable myocardium with low doses of dobutamine.
Clinical Implications
Because it is characteristic of viable
(hibernating/stunned) myocardial regions supplied by a
significant coronary stenosis and the best
parameter to predict functional recovery after
revascularization,7,9 the
biphasic response of wall thickening with initial improvement
(recruitable contractile reserve) and subsequent deterioration
(inducible ischemia) during incremental dobutamine
infusion has been increasingly used clinically as a marker of viable
myocardium with inducible ischemia. This study
showed that the combination of low-dose dobutamine and
nitroglycerin augments wall thickening to a
significantly greater degree than either drug alone in hibernating
myocardium subtending severe coronary
stenosis or viable (stunned/hibernating) myocardium
around the infarcted (peri-infarcted) region supplied by a significant
residual stenosis. Furthermore, this study demonstrated that
nitroglycerin did not prevent hibernating
myocardium from ischemia with deterioration of
regional wall thickening induced by high doses of
dobutamine infusion. Therefore,
nitroglycerin augments the biphasic response of wall
thickening in the hibernating or stunned region supplied by a
significant coronary stenosis, and the combination of
nitroglycerin and dobutamine should be
tested clinically to improve the sensitivity and accuracy of
dobutamine stress echocardiography for
the detection of hibernating or stunned myocardium with a
significant residual coronary stenosis.
|
Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study is supported by Hartford Hospital Research Fund. The authors appreciate the excellent technical assistance provided by William Dyckman and Edward Hall.
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Footnotes |
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This study was presented in part at the 69th Scientific Sessions of American Heart Association, November 15, 1995, Anaheim, Calif, and in part at the 46th Scientific Session of American College of Cardiology, March 24, 1996, Orlando, Fl.
Received February 6, 1997; revision received August 18, 1997; accepted August 28, 1997.
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