© 1995 American Heart Association, Inc.
Articles |
Mechanism of Impaired Myocardial Function During Progressive Coronary Stenosis in Conscious Pigs
Hibernation Versus Stunning?
From the Departments of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Mass, and the New England Regional Primate Research Center, Southborough, Mass.
Correspondence to Stephen F. Vatner, MD, Professor of Medicine, Harvard Medical School, New England Regional Primate Research Center, One Pine Hill Drive, PO Box 9102, Southborough, MA 01772-9102.
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Abstract |
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Abstract The major goal of this study was to determine whether impaired myocardial contractile function during the development of progressive coronary artery stenosis induced by ameroid constriction in conscious pigs reflected myocardial "hibernation" or "stunning." Minipigs were instrumented with a coronary ameroid constrictor and hydraulic occluder, regional wall thickness crystals, a left ventricular (LV) pressure gauge, and aortic and left atrial catheters. In the seven pigs in which it was measured, systolic wall thickening (WT) distal to the ameroid fell by a maximum of 56±6% at 20±3 days after ameroid implantation and then began to recover. At 1 day after ameroid implantation, brief complete coronary artery occlusion (CAO) resulted in wall thinning distal to the ameroid (-113±4%) and transmural decreases in myocardial blood flow in endocardial (from 0.82±0.08 to 0.02±0.01 mL/min per gram) and epicardial (from 0.73±0.13 to 0.03±0.02 mL/min per gram) layers. At 20±3 days, baseline myocardial blood flow was not altered either in endocardial (0.92±0.10 mL/min per gram) or epicardial (0.85±0.12 mL/min per gram) layers, whereas brief complete coronary artery occlusion still reduced WT (-83±12%) and myocardial blood flow in endocardial (to 0.21±0.03 mL/min per gram) and epicardial (to 0.43±0.12 mL/min per gram) layers, indicating that the coronary artery was not totally occluded. Pathology in four pigs demonstrated no gross necrotic myocardium shortly after this time point. Transient reductions in WT distal to the ameroid were observed during progressive coronary artery stenosis in response to spontaneous increases in activity. Beat-by-beat analysis of these episodes revealed that acute reductions in WT followed increases in LV dP/dt and heart rate and exhibited delayed recovery. These data suggest that the reduced function during ameroid-induced coronary stenosis reflected cumulative myocardial stunning rather than a primary deficit in coronary blood flow or "hibernating myocardium."
Key Words: myocardial blood flow • regional myocardial function • ischemia • oxygen supply/demand • ameroid constrictor
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Introduction |
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Recently, "hibernating myocardium" has attracted considerable interest as a concept to explain depressed myocardial contractile function in the face of reduced myocardial perfusion, which can be reversed with restoration of myocardial blood flow.1 2 3 4 One potential model of hibernating myocardium involves progressive but gradual coronary artery stenosis, such as occurs with ameroid coronary constriction, particularly since prior studies suggested that chronic coronary artery stenosis results in sustained depression of myocardial contractile function in experimental animal models5 6 7 8 and in clinical situations.1 9 10 Since rapid coronary collateralization can prevent a sustained reduction in regional myocardial function during ameroid coronary constriction in dogs, the present studies were conducted in an animal model devoid of preformed coronary collaterals, ie, pigs.
The initial goal of the present study was to characterize the time course and the pattern of regional myocardial contractile function during the development of progressive coronary artery stenosis in conscious pigs, since most prior studies on this topic have only collected infrequent measurements. To accomplish this goal, daily (n=5) or semiweekly (n=2) measurements of global hemodynamics and regional myocardial function were performed beginning 1 day after implantation of the ameroid constrictor. The frequent monitoring sessions also permitted examination of responses of regional myocardial function to spontaneous episodes of stress, as occur naturally with eating or movement. The second goal was to determine whether the reduced contractile dysfunction was secondary to reduced regional myocardial perfusion (hibernating myocardium). The third goal was to determine the time course of development of the collateral circulation. To address these latter goals, the radioactive microsphere technique was used with and without the coronary artery temporarily occluded. This latter maneuver allowed direct assessment of collateral blood flow in the distribution of the coronary artery with the ameroid constriction.
Recognizing the interanimal variable nature of ameroid closure, an important feature of the current experimental design was the analysis of regional myocardial function, blood flow, and collateral development at the nadir of function rather than a specific time after implantation of the ameroid device. An additional potential problem in the interpretation of prior studies on the topic of hibernating myocardium is that the area of measurement of regional myocardial function and blood flow might contain a substantial area of necrosis. Accordingly, the extent to which gross infarction occurred was examined in four of the animals shortly after the peak reduction in regional wall thickening and in five of the remaining animals at a later point after collaterals had developed more extensively.
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Materials and Methods |
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Ten minipigs (Charles River Inc, Boston, Mass), weighing 26.1±2.5 kg, were sedated with telazol (5 mg/kg IM) and atropine (0.05 mg/kg IM). General anesthesia was induced with sodium thiamylal (10 to 20 mg/kg IV) and then intubated and maintained with halothane (0.5 to 1.5 vol%). By use of sterile surgical technique, a left thoracotomy was performed at the fifth intercostal space. Tygon catheters (Norton Plastics) were implanted in the descending aorta and in the left atrium for measurement of pressures and radioactive microsphere injection. A solid-state miniature pressure gauge was implanted in the left ventricular (LV) cavity to obtain LV pressure and dP/dt. The left circumflex coronary artery was isolated, and an ameroid constrictor and a hydraulic occluder, made of polyethylene tubing, were implanted in six of the pigs, whereas in one pig, the left anterior descending coronary artery was instrumented. In that latter pig, transonic flow transducers were implanted on both the left anterior descending and left circumflex coronary arteries for continuous measurement of coronary blood flow in both regions. In all pigs, two pairs of ultrasonic crystals were implanted transmurally across the LV free wall, in the anterior and in the posterior regions, for measurement of regional wall thickness. The subendocardial crystal was introduced obliquely, so that the myocardium between the two crystals would not be impaired by injury or fibrosis. Proper alignment of the epicardial and endocardial crystals was achieved during surgical implantation by positioning the crystals to obtain a received signal on the oscilloscope with the greatest amplitude and shortest transit time. It is also important to note that the crystals distal to the ameroid were implanted in the central ischemic zone, as defined by a test coronary artery occlusion at the time of operation. The correct placement of the crystals was also confirmed at autopsy. The wires and catheters were externalized between the scapulae, the incision was closed in layers, and the chest was evacuated. Each pig was treated with 1 g cephalothin (Keflin, Lilly) immediately after surgery and for 1 week after surgery. Animals used in the present study were maintained in accordance with the guideline of the Committee on Animals of the Harvard Medical School and the "Guide for the Care and Use of Laboratory Animals" (Department of Health and Human Services publication No. [NIH] 85-23, revised 1985). An additional five pigs could not be studied: one occluded rapidly and developed myocardial infarction, one was observed to have a severe coronary stenosis immediately after surgery that was due to improper instrumentation, two never developed a severe coronary stenosis and evidence of regional dysfunction, and one did not recover from ventricular fibrillation during the 2-minute coronary arterial occlusion at 1 day after ameroid implantation.
Hemodynamics were recorded continuously on a magnetic tape recorder (Honeywell) and played back on a multiple-channel ink-writing oscillograph (Gould-Brush). Aortic and left atrial pressures were measured with a strain-gauge manometer (Statham Instruments) connected to the respective fluid-filled catheters. The solid-state LV pressure gauge was cross-calibrated against measurements of systolic aortic and left atrial pressures. LV dP/dt was calculated with an operational amplifier connected as a differentiator, which has a frequency response of 700 Hz. Mean arterial pressure was determined by using a resistance-capacitance filter having a 2-second time constant. Regional myocardial function was measured with an ultrasonic transit-time dimension gauge. This instrument measures the transit time of acoustic signals traveling at a sonic velocity of 1.58x106 mm/s between the intramyocardial crystal pairs. The drift of this instrument, although minimal, was effectively compensated for by repeated calibrations. A cardiotachometer triggered by the LV pressure pulse provided instantaneous and continuous recordings of heart rate.
All pigs were introduced to a sling for training 1 to 2 hours daily over a 1- to 2-week period before surgery. The experiments in conscious unsedated pigs were initiated 1 day after surgery, when the animals had recovered from anesthesia. Global and regional hemodynamic data were recorded for at least 30 to 60 minutes on the first day and daily thereafter in five pigs and semiweekly thereafter in two pigs. In three pigs hemodynamic data were recorded only at 1 day and at 1 month after surgery, with random measurements in between. These latter three pigs were used for later measurements (1 month) of time of blood flow and function. Regional blood flow was measured by the radioactive microsphere technique. Two to three million microspheres (15±1 µm) labeled with 95Nb, 85Sr, 141Ce, 46Sc, 113Tin, 51Cr, 114In, and 103Ru were suspended in 0.01% Tween 80 solution (10% dextran) and placed in an ultrasonic bath for 30 to 60 minutes. Before the first injection of microspheres, 1 mL of Tween 80 solution was injected to test for potential adverse cardiovascular effects. Microspheres were injected and flushed with saline over a 20-second period via the left atrial catheter. Arterial blood reference samples were withdrawn at a rate of 7.75 mL/min for a total of 120 seconds. Radioactive microspheres were administered (1) at baseline (ie, day 1), during a 2-minute period of acute coronary artery occlusion, which was induced by inflating the hydraulic occluder, (2) on the day of peak reduction in wall thickening distal to the ameroid, and (3) just before the animals were killed for study.
At the end of the experiments, the animals were anesthetized with
pentobarbital (30 to 50 mg/kg IV), and the heart was excised and placed
on a perfusion apparatus. In four of the animals, this procedure was
carried out from 2 to 7 days after the peak reduction in wall
thickening. The ascending aorta was cannulated (distal to the sinus of
Valsalva) and perfused retrogradely with Evans blue dye (0.1%
solution). The coronary artery was cannulated at the site of occlusion
and perfused with saline. The driving pressure was maintained at 
120
to 150 mm Hg for both cannulas. After completion of perfusion, the LV
was cut into eight or nine slices, and the apical surface of individual
rings was photographed for identification of the anatomic area at risk.
After this procedure, three of the four hearts were incubated in
triphenyltetrazolium chloride (TTC) in phosphate buffer solution. For
measurement of regional myocardial blood flow, the rings were cut
further into 200 pieces for the entire heart, with each piece
weighing an average of 0.30±0.03 g. The total weight of tissue for
each animal averaged 42.1±6.0 g for the contralateral region and
10.3±1.7 g for the region distal to the ameroid. The samples were
counted in a gamma counter (Searle Analytical) with appropriately
selected energy windows. After correction of counts for background and
crossover, regional myocardial blood flow was obtained and expressed as
milliliters per minute per gram of tissue. Data for blood flow are
reported for the area distal to the ameroid and contralateral to the
ameroid. Only the tissue at the interface of the two zones was
excluded. The remaining tissue, within the area distal to the ameroid,
demonstrated blood flow of <0.12 mL/min per gram during the first
coronary artery occlusion.
The functional area at risk was calculated on the basis of these blood flow measurements during the initial brief coronary artery occlusion. Since it was assumed that tissue samples with >80% blood flow reduction during acute coronary artery occlusion reflected complete risk and tissue samples with blood flow reductions ranging from 0% to 80% reflected that percentage of tissue at risk, the entire area at risk could be reconstructed and quantified. The functional area at risk was assessed from the initial coronary artery occlusion. At intermediate and later time points, these techniques were used to provide an in vivo expression of the development of collateralization, by examining the decrease in total flow deficit induced by brief coronary artery occlusion.
All data were stored on a PC computer. The data of regional as well as systemic hemodynamics were monitored daily but averaged semiweekly. Additionally, the data on regional function were also referenced to the time of maximal reduction in wall thickening distal to the ameroid. To accomplish this, the data were averaged on the day of maximal reduction in wall thickening distal to the ameroid and at semiweekly intervals before and after that time point. Comparisons between baseline (1 day after ameroid implantation) and multiple responses were performed by repeated-measures ANOVA with analysis of contrasts for individual comparisons. A value of P<.05 was considered significant. All values are expressed as mean±SEM.
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Results |
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Tables 1 through 3
compare data at the time of peak reduction in
regional function (20±3 days) and during the last measurement (34±2
days). For each of these time points, the data are compared with the
respective data in the same pigs at day 1 after recovery from
surgery.
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Global and Regional Hemodynamics During Development of Progressive
Coronary Artery Stenosis
The baseline values for systemic hemodynamics obtained on day 1
after implantation of the ameroid constrictor, at the time of peak
reduction in wall motion (20±3 days), and during the last measurement
(34±2 days) are shown in Table 1
. At 1 week, minor
increases in LV systolic pressure (+13±4%), LV dP/dt (24±11%), and
mean arterial pressure (11±6%) were observed, most likely reflecting
further recovery from the thoracotomy. At the time of peak reduction in
regional function (20±3 days), only heart rate was elevated. During
the last measurement (34±2 days), heart rate was no longer elevated,
but modest increases in pressure and LV dP/dt were observed. Sustained
arrhythmias were not observed during any of the monitoring periods.
Representative phasic waveforms of LV pressure, LV dP/dt, and
regional wall thicknesses are illustrated in a conscious pig during the
development of progressive coronary artery stenosis (Fig 1). In this animal, the peak reduction in systolic wall
thickening distal to the ameroid occurred 18 days after implantation of
the ameroid constrictor. The impaired wall motion then recovered
partially at 30 days. The serial changes in systolic wall thickening
are summarized in seven conscious pigs in Fig 2. The
variability in time of peak reduction in wall thickening is shown at
the top of Fig 2, which depicts the serial changes at fixed time points
after ameroid implantation. At the bottom of Fig 2, the time of maximal
reduction in systolic wall thickening is used as the reference point.
The peak reduction of systolic wall thickening (-56±6.1%) occurred
at 20±3 days and then recovered toward the control level. The average
changes for regional wall thicknesses at 20±3 days and 34±2 days
compared with their respective control values at day 1 are shown in
Table 2. Systolic wall thickening distal to the ameroid
began to fall after 1 week, reached a nadir of 56±6.1% below baseline
at 20±3 days (P<.05), began to recover, and was no longer
significantly depressed at 34±2 days.
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Myocardial Blood Flow
The values of regional myocardial blood flow in both walls on the
day when the peak reduction of regional myocardial function occurred
and during the last measurement are compared with their respective
control values at day 1 in Table 3. At 1 day after
ameroid implantation, similar transmural myocardial blood flows were
measured distal to the ameroid and contralateral regions. These values
were again similar during the time of peak reduction of systolic wall
thickening (20±3 days) (0.91±0.10 versus 0.97±0.13 mL/min per gram)
and at 34±2 days, when recovery of function and nearly full
collateralization had occurred (1.03±0.13 versus 1.00±0.13 mL/min per
gram). The levels of subendocardial, subepicardial, and midmyocardial
blood flow were also observed to be similar at these time points in
both walls (Table 3).
Relation Between Blood Flow and Function
In seven pigs, 13 measurements of endocardial blood flow
bracketing the time of peak reduction in wall thickening were made.
These data are displayed in Fig 3. In none of the
measurements was subendocardial blood flow reduced substantially during
the time of major reduction in wall thickening, ranging from 27% to
81% in the 13 measurements. The data were also analyzed by comparing
the ameroid region–to–contralateral region (ameroid/contralateral)
ratio for blood flow with the ratio for changes in function (wall
thickening) at 20±3 (n=7) and 34±2 (n=8) days after ameroid
implantation. These data are shown in Fig 4 for
endocardial blood flow (top) and transmural blood flow (bottom). In
both instances, it is clear that the decrease in function is far out of
proportion to any potential decrease in blood flow, arguing against the
possibility of hibernating myocardium. For example, the ratio of
subendocardial blood flow (ameroid/contralateral) was reduced
insignificantly, by 7.3±8.4% at 20±3 days and by 9.4±4.9% at 34±2
days, whereas the ratio of wall thickening in these regions was reduced
more (P<.05), by 57.7±6.9% at 20±3 days and by
28.1±6.8% at 34±2 days.
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Effects of Brief Complete Coronary Artery Occlusion on Regional
Myocardial Function and Blood Flow
The effects of brief complete coronary artery occlusion for 2
minutes on regional myocardial function at day 1, days 20±3, and days
32±2 are shown in Fig 5. Coronary artery occlusion
reduced systolic wall thickening by 113±3.8% at day 1 after ameroid
implantation. At 20±3 days, when the baseline value of systolic wall
thickening was maximally depressed, coronary artery occlusion still
resulted in a further reduction in systolic wall thickening
(83±12.4%). However, during the later time period after ameroid
implantation, coronary artery occlusion reduced systolic wall
thickening by only 36±20.4%. In all experiments, coronary artery
occlusion did not alter systolic wall thickening in the contralateral
wall.
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The effects of brief complete coronary artery occlusion on regional
myocardial blood flow distal to the ameroid in endocardial and
epicardial layers are demonstrated in Fig 6. Coronary
artery occlusion significantly reduced regional blood flow in
endocardial layers (to 0.02±0.01 mL/min per gram) and epicardial
layers (to 0.03±0.02 mL/min per gram) on the first day after
implantation of the ameroid. At 20±3 days, when the baseline systolic
wall thickening was maximally depressed, coronary artery occlusion
still decreased myocardial blood flow in endocardial layers (to
0.21±0.03 mL/min per gram) and epicardial layers (to 0.43±0.12 mL/min
per gram), which was less (P<.05) than at day 1. During the
later time period, coronary artery occlusion still decreased myocardial
blood flow in the endocardial layer (to 0.53±0.09 mL/min per gram),
but this was less (P<.05) compared with that at 20±3 days,
whereas myocardial blood flow was decreased only slightly in the
epicardial layer (to 0.76±0.21 mL/min per gram).
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Effects of Transient Spontaneous Excitement
Daily recordings demonstrated that the reduced systolic wall
thickening distal to the ameroid was not progressive but episodic, but
blood flow in the region distal to the ameroid did not fall (Fig 7). Note that as early as 6 days after implantation of
the ameroid constrictor, systolic wall thickening distal to the ameroid
was reduced markedly but recovered quickly. The second reduction in
systolic wall thickening was observed at 10 days, and the third
sustained reduction in systolic wall thickening occurred at 15 days.
The daily recordings are graphed from another pig in Fig 8. Note that the transient reductions in systolic wall
thickening distal to the ameroid occurred in the posterior wall at 8,
14, and 20 days after ameroid implantation. The earlier reductions in
systolic wall thickening at 8 and 14 days were reversible, whereas the
later reductions were not fully reversible. Systolic wall
thickening in the contralateral region did not change significantly
throughout the monitoring period. When these periods of reversible
dysfunction were examined, it was observed that they closely followed
brief periods of excitement. Representative waveforms of LV
pressure, LV dP/dt, and wall thicknesses in a conscious pig during
excitement at 16 days after ameroid implantation are shown in Fig 9. It is important to note that during early excitement,
LV dP/dt, heart rate, and both wall thicknesses rose. Later, when LV
dP/dt and heart rate returned toward control levels and the animal was
no longer excited, systolic wall thickening distal to the ameroid fell
below baseline levels. Beat-to-beat analyses of LV dP/dt, heart rate,
and systolic wall thickening in a conscious pig before and after the
brief period of excitement are demonstrated in Fig 10.
In Fig 11, a longer period (2 minutes) of excitement
is analyzed, which required over 30 minutes for systolic wall
thickening to recover. These analyses indicate that the regional wall
dysfunction clearly follows the changes in heart rate and LV dP/dt, ie,
factors that affect myocardial oxygen demand. A prolonged reduction in
systolic wall thickening induced by multiple repetitive episodes of
spontaneous excitement is shown in Fig 12. In contrast
to what was observed during brief reversible excitement, repetitive
episodes of spontaneous excitement resulted in cumulative prolonged
depression of systolic wall thickening, which lasted hours. It is
important to point out that during the fourth bout of excitement, which
lasted 135 seconds, systolic wall thickening was reduced by 109% (ie,
it reflected paradoxical motion), and wall motion did not even recover
2 days later.
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), heart rate
(
), and systolic wall thickening (WT) distal to
the ameroid (
) and in the contralateral regions (
) in a
conscious pig during spontaneous excitement, the duration of which is
denoted by the arrows. Values are expressed as percent change from
control, ie, before excitement. Increases in LV dP/dt and heart rate
were observed almost immediately after the inception of excitement.
However, the reduction in systolic WT distal to the ameroid followed
the increase in heart rate and LV dP/dt and did not begin until after
excitement had terminated. This suggests that the functional deficit
was caused by an imbalance in oxygen supply and demand in response to
the hemodynamic changes rather than by a primary reduction in coronary
blood flow.
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Pathological Measurements and Assessment of Functional Area at
Risk
In four pigs, pathology was examined at 3±1 days after the peak
reduction in wall thickening. TTC staining in three pigs revealed no
visible loss of stain, indicating no gross necrotic lesions, although
focal microscopic areas of necrosis could not be excluded. In one pig,
TTC was not used, but the heart was sectioned and examined for
necrosis. In that heart, there also were no gross infarcted regions. In
five pigs, pathology was examined at 18±3 days after the peak
reduction in wall thickening. Histology in these five pigs revealed
patchy areas of subendocardial fibrosis.
The functional area at risk was also measured by using the
radioactive microsphere technique to assess the extent of blood flow
reduction with acute coronary artery occlusion early (1 day) after
ameroid implantation. The total flow deficit during acute coronary
occlusion was also measured during the time of maximal reduction in
wall motion (20±3 days) and just before death. At day 1, the
functional area of risk constituted 24.7±3.0% of the LV. The fraction
of total flow deficit during coronary artery occlusion was reduced by
48±8.9% at 20±3 days after ameroid implantation and by 75±11.9% at
the later time period. As shown in Fig 6, brief coronary artery
occlusion during the later time period failed to reduce subepicardial
blood flow but did modestly reduce subendocardial blood flow,
suggesting that full collateralization had occurred in the
subepicardium.
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Discussion |
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The initial goal of the present investigation was to examine the time course and extent of the reduction of regional myocardial function in conscious pigs during the development of progressive coronary artery stenosis induced by ameroid coronary constriction. After a transient rise in regional function during the first week, which could have been due to additional recovery from the effects of surgery, regional myocardial function fell by a maximum of 56% at 20±3 days after ameroid implantation. The magnitude of impairment in wall motion far exceeded that in prior studies of ameroid coronary constriction. It is difficult to completely reconcile these differences since no prior study used an identical experimental design. Prior studies in dogs found no absolute reduction in regional function in the collateral-dependent zone,6 11 12 which could be predicted because of the rapid collateralization that occurs in dogs with ameroid coronary occlusion. However, prior studies in pigs also failed to note such a major reduction in regional function.7 13 14 15 16 It must be noted that the extent to which progressive coronary stenosis affected regional myocardial function was not a major focus of those studies. Accordingly, these differences can be attributed, in part, to the failure to record serial measurements or the lack of baseline measurements before the beginning of the constriction process. For example, in many prior studies of ameroid constriction in pigs, the initial measurement was made 3 to 6 weeks after ameroid implantation.13 14 15 16 At this point in the process, the present study also failed to observe a significant reduction in wall motion in the collateral-dependent zone. Additionally, the present investigation, by design, selected the maximum point of reduction of function rather than the fall in function at any specific time point to minimize interanimal variability in ameroid closure time. By using this normalization procedure, we were able to demonstrate more severe reduction in regional myocardial function than that found in prior studies of this topic. Thus, the differences in our results and those of prior studies can be attributed to rapid collateralization in dogs, whereas in pigs the differences are likely due to the absence of serial measurements, particularly a measurement soon after ameroid implantation, and the lack of normalization of data, which is necessary to minimize the variability inherent to the different times of ameroid closure among animals.
Next, it was considered important to determine the mechanism of the
dysfunction. Since it has been reported that ameroid-induced chronic
coronary constriction leading to occlusion in pigs results in a
variable amount of infarction, ranging from focal microscopic lesions
to 5% to 25% of the area at risk,7 13 14 15 16 17 18 19 20 it was
important to rule out this possible cause of the reduction in regional
myocardial function. In the present study, examination (including
TTC staining) of the myocardium a few days after the peak reduction in
systolic wall thickening indicated no visible gross necrotic tissue.
This does not exclude the likely possibility of spotty subendocardial
fibrotic lesions at the microscopic level16 19 or more
severe lesions later in the process, as noted by others at later time
periods.14 15 Indeed, we did observe patchy areas of
subendocardial fibrosis at the later time period. It is for this reason
that the mechanism of the small decrease in subendocardial blood flow,
when analyzed as a ratio of contralateral zone blood flow, observed at
this point cannot be ascertained (Fig 4, Table 3). This modest decrease
in blood flow ratio (9.4±4.9%) was significantly less
(P<.05) than the decrease in function ratio (28±7%) and
could have been due to the infarction or to sustained myocardial
"stunning." It is for this reason that the major conclusions of
the present investigation must rely on the data obtained at 20±3
days, ie, during the time of peak reduction in wall thickening, which
was not accompanied by any significant infarction or by any substantive
decrease in either subendocardial or transmural blood flow (Figs 3 and 4).
The main purpose of the present study was to determine whether the
impaired regional myocardial function (56±6% in systolic wall
thickening) observed with ameroid coronary stenosis was due to
"myocardial hibernation." The "smart heart" hypothesis has
been proposed to explain hibernating myocardium,1 whereby
the myocardium downgrades its function in response to reduced
myocardial perfusion at rest.3 A sine qua non for
myocardial hibernation is the reduced blood flow in the area of
myocardium with depressed function. For example, with acute coronary
stenosis a 60% reduction in regional myocardial function is associated
with an 75% reduction in regional myocardial blood
flow.21 To address this hypothesis directly in the
present investigation, radioactive microspheres were administered
at baseline and simultaneously with peak reduction in systolic wall
thickening at 20±3 days after ameroid implantation. The results of
these experiments indicated that the blood flows in endocardial,
midmyocardial, and epicardial layers were essentially at normal levels;
ie, there were no differences between the data obtained at 1 day after
ameroid implantation and at the time of peak depression of function,
rendering unlikely the possibility that the reduced function reflected
hibernating myocardium. This is most convincingly shown in Fig 3, in
which 13 simultaneous measurements of subendocardial blood flow
demonstrate no significant reduction, whereas there were major
reductions in wall thickening, ranging from 27% to 81%. In most other
prior studies in pigs with ameroid coronary constriction, decreases in
blood flow were recorded7 13 14 15 that were associated
either with no change13 14 15 or with a
reduction7 in regional wall motion. The decreases in blood
flow in these studies may have been due to the later time of
measurement and potentially greater collateral dependence or most
likely to more severe necrosis in the ameroid-dependent zone.
It could be argued that in the present study the ameroid device completely occluded the coronary artery and the distal myocardium maintained its flow entirely by collateralized channels. To address this concern, the coronary artery was temporarily occluded at the time of peak reduction in regional myocardial function. These experiments demonstrated that the coronary artery was still patent and that collateralization had only been initiated. In contrast, at 32±2 days after ameroid coronary implantation, collateralization was more complete but variable, in that measurements of regional myocardial function fell by 36±20% during a temporary coronary artery occlusion.
In view of all of the above, our present hypothesis is that the
reduction in regional wall motion reflects the consequences of repeated
cumulative imbalances between regional oxygen demand and supply,
resulting in chronic myocardial stunning, a variant of acute myocardial
stunning, which has been recognized for 20 years.22 23 24
Chronic myocardial stunning could have been induced by frequent
transient episodes of intense imbalance between oxygen supply and
demand. The serial recordings support this conclusion: a characteristic
finding in the present investigation was repeated episodes of
myocardial dysfunction following brief periods of spontaneous arousal
(eg, motion, eating, and excitement). These spontaneous episodes of
reversible myocardial dysfunction induced by spontaneous excitement
were frequent during the phase just before the peak reduction in
regional myocardial function. As demonstrated in Fig 10, one episode of
excitement for only 10 to 15 seconds resulted in a more prolonged
decline in regional function, whereas multiple episodes resulted in
sustained depression of function (Fig 12). With multiple episodes, the
stunning becomes accumulative, and recovery of function is prolonged
even further, such that eventually full recovery is not possible.
The timing of the episodic transient reductions in wall motion
following periods of excitement argue against a primary role of
coronary blood flow reduction. Specifically, if the transient reduction
in regional wall motion was secondary to reduced coronary blood flow,
then the increases in heart rate and LV dP/dt should be coincident with
or follow the reduction in function. However, since the reverse was
observed (ie, increases in heart rate and LV dP/dt clearly preceded the
fall in regional function [Figs 9 through 11]), it is more likely
that the mechanism of the dysfunction is due to an imbalance between
oxygen demand and supply rather than to a primary blood flow reduction,
which could be induced by cyclical platelet clumps25 26 or
more severe constriction of the epicardial coronary artery.
Prior studies have also speculated that myocardial stunning may be the mechanism for chronic reduced function in the absence of a major flow deficit.6 9 However, those studies lacked quantitative data and direct evidence of episodic dysfunction, which were included in the present investigation. All of these studies do not exclude the existence of hibernating myocardium but indicate that not all examples of sustained reduction in regional myocardial function distal to a severe coronary stenosis and in the absence of myocardial necrosis are due to hibernation.
Alternatively, the definition of hibernating myocardium needs to be reconsidered. It is likely that had the stenosis been removed at 20±3 days in the ameroid model used in the present investigation, when there was no necrosis, function would have recovered rapidly and completely, characteristic of hibernating myocardium. The results of the present investigation suggest that there may be a blurring of definitions between myocardial hibernation and myocardial stunning (ie, that the two conditions may coexist or may actually share the same mechanism). However, it is recognized that it is also difficult to generalize to a complex clinical syndrome such as hibernating myocardium by using just one animal model of chronic progressive coronary stenosis in the absence of atherosclerosis.
Finally, several prior studies have examined collateral development in
pigs with ameroid coronary constriction.13 14 15 16 17 18 19 20 This model
is particularly useful because it is devoid of preformed coronary
collaterals. However, no prior study has tracked the development of
collaterals in vivo. In the present study, this was accomplished by
examining the diminishing functional deficit of blood flow within the
area at risk assessed with regional blood flow measurements during
brief complete coronary artery occlusion. This relation could
potentially serve as a powerful model for the future study of agents
that affect collateral development. As shown in Fig 6, brief complete
coronary artery occlusion reduced subepicardial flow less than
subendocardial blood flow after collateralization had started. At the
later time point, there was essentially no reduction in subepicardial
blood flow with brief coronary artery occlusion, suggesting that
collateralization was almost fully developed subepicardially. Thus, the
collaterals, as demonstrated by this technique, developed first and
more fully in the subepicardium, despite the concept that anatomic
subendocardial collaterals are thought to develop earlier in the
pig.27
In conclusion, in conscious pigs with progressive coronary artery stenosis, severe myocardial contractile dysfunction was observed. This was most evident when interanimal variability was minimized by a combination of serial recordings and selecting the time of maximal reduction in wall thickening as a reference. The severe contractile dysfunction observed appears to reflect chronic myocardial stunning, potentially due to frequent transient periods of imbalance of oxygen supply and demand induced by naturally occurring episodes of excitement and arousal rather than to hibernating myocardium or myocardial necrosis. Although the results from the present investigation answer several questions, the questions raised are equally as important. Most important, in the face of chronic severe contractile dysfunction, why wasn't blood flow reduced? This would seem to be the perfect setting for hibernation, but blood flow was maintained, suggesting that autoregulatory forces predominated. Thus, the results of the present investigation call into question the physiological basis, underlying mechanisms, or potentially the definition of hibernating myocardium. The results of the present investigation suggest that myocardial hibernation and myocardial stunning may coexist or share a common mechanism or that cases considered to be hibernating myocardium may actually reflect chronic repeated stunning.
|
Acknowledgments |
|---|
This study was supported in part by US Public Health Service grants HL-33065, HL-38070, HL-33107, HL-45332, and RR-00168.
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Footnotes |
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This manuscript was sent to Francois M. Abboud, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Received May 13, 1994; accepted November 21, 1994.
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References |
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