Myocardial Adaptation During and After Sustained, Demand-Induced Ischemia
Observations in Closed-Chest, Domestic Swine
Background We tested the hypotheses that prolonged, demand-induced myocardial ischemia plateaus and that on relief of stress, myocardial function remains depressed, with proportionate reductions in blood flow and oxygen consumption indicative of hibernation.
Methods and Results Closed-chest swine (n=20) were prepared with an 80% coronary stenosis. Hemodynamics, myocardial blood flow, oxygen, and lactate metabolism were measured in group 1 (n=9) (1) at baseline, (2) at 10 and 30 minutes of atrial pacing plus intravenous norepinephrine infusion, and (3) in 5 of 9 (group 1a) at ≈50 minutes after stress. Group 1a had ischemia assessed with 99mTc-labeled BMS 181321. In group 2 (n=11), myocardial function was determined with radionuclide ventriculography (n=8), and myocardial necrosis was looked for with trichlorotetrazolium chloride staining (n=7), histology (n=10), and myocardial creatine kinase concentration (n=4). Baseline stenotic-zone endocardial blood flow was reduced versus the normal zone (0.94±0.33 versus 1.38±0.27 mL·min−1·g−1, mean±SD; P<.05), whereas epicardial flows were comparable (1.15±0.36 versus 1.16±0.26 mL·min−1·g−1). Stenotic-zone endocardial flow was unchanged versus baseline at 10 and 30 minutes of stress, whereas epicardial flow increased (1.62±0.53 mL·min−1·g−1 at 10 minutes and 1.44±0.51 mL·min−1·g−1 at 30 minutes, both P<.05). Myocardial oxygen consumption increased versus baseline (10.8±2.9 mL·min−1·100 g−1) at 10 and 30 minutes of stress (14.9±5.2 and 13.9±4.5 mL·min−1·100 g−1, both P<.05). After stress, stenotic-zone blood flow and oxygen consumption were reduced ≈30% (P<.01) versus baseline. In group 2, stenotic-zone contraction with stress declined versus baseline and remained depressed throughout recovery. Histological and biochemical evidence of myocardial necrosis was absent in group 2.
Conclusions Myocardial ischemia induced by a sustained increase in oxygen demand may not progress to necrosis but may instead plateau. After relief of stress, myocardial function remains depressed, with a proportionate reduction in blood flow and oxygen consumption consistent with myocardial hibernation.
Recognition of myocardial hibernation1 2 3 4 5 6 7 8 9 10 and stunning11 12 13 in both clinical and laboratory settings has fostered interest in the mechanisms that underlie these phenomena and in identification of clinically relevant circumstances that may lead to their development. Thus, although brief coronary artery occlusion with subsequent reperfusion is known to cause myocardial stunning11 and prolonged mild to moderate reduction in flow hibernation,1 2 7 9 the myocardial metabolic response to sustained demand-induced ischemia with preservation (or even augmentation) of MBF is unknown. It is known that recovery of segmental shortening is impaired after pacing-induced ischemia in a swine model of coronary artery stenosis.14 However, the degree of functional impairment, which is mild to moderate, is no different after 5 minutes of pacing stress than it is after 30 minutes of pacing.14 These observations suggest the hypotheses that myocardial metabolic responses to prolonged stress-induced ischemia with preserved or augmented blood flow will exhibit evidence of adaptation rather than deterioration over time and that prolonged ischemia does not necessarily go on to myocardial infarction. The earlier data on prolonged versus brief pacing stress14 also suggest the hypothesis that myocardial hibernation may be induced by prolonged stress, since recovery of function was incomplete after relief of stress. The present study was performed to test each of these hypotheses. Experiments were conducted in closed-chest, domestic swine instrumented with an artificial stenosis that reduced lumen diameter of the LAD by 80%.1 14 15
Farm-bred domestic swine (n=20; mean weight, 46 kg; range, 30 to 55 kg) were premedicated with ketamine (25 mg/kg IM) and sodium thiamylol (total dose, 0.5 to 1.0 g IV), intubated, and anesthetized with halothane (0.5% to 1.5%) and nitrous oxide (60:40 mixture with oxygen). Arterial blood gases were monitored frequently and were maintained at appropriate levels throughout each study (Po2, 148±28 mm Hg; Pco2, 38±3 mm Hg; mean±SD). After induction of anesthesia, each animal was anticoagulated with heparin (225 IU/kg IV). Full anticoagulation was maintained by giving half the loading dose of heparin every 2 hours.
In each group 1 animal, a 7F pigtail catheter was advanced under fluoroscopic guidance into the left atrium to administer colored microspheres for measurement of regional MBF. In group 2 animals, the catheter was positioned in the left ventricle to monitor pressure during the study. An 8F catheter was positioned in the aorta to monitor arterial blood gases (all animals) and for reference withdrawal for microsphere determinations of regional MBF (group 1). The femoral veins were cannulated bilaterally to administer fluids and medications during the study. Catheters were advanced, via the internal and external jugular veins, respectively, into the coronary sinus (7F, pacing) and into the AIV (3F, end hole). An artificial stenosis that reduced vessel diameter by 80% was positioned in the proximal third of the LAD1 14 15 via the internal carotid artery. After placement of the stenosis, halothane and nitrous oxide were discontinued, and the animal was permitted to awaken sufficiently to breathe spontaneously and exhibit modest tremulousness. A constant intravenous infusion of sodium thiamylol was begun at 5 to 25 mL/h (20 mg/mL) to maintain light anesthesia and ensure that the animal was free of pain.
Heart rate and arterial, left atrial (or left ventricular), and coronary pressures were monitored continuously and recorded electronically with a Macintosh computer system and commercially available hardware (MP100WS system; World Precision Instruments) and software (Acknowledge) in group 1 and with a Hewlett-Packard eight-channel recorder in group 2. Intravascular and intracardiac pressures were recorded from fluid-filled catheters connected to Cobe model 049924 force transducers.
Group 1 (n=9)
After a minimum 30-minute stabilization interval after instrumentation (average ≈60 minutes), the protocol was begun. Baseline measurements of hemodynamics, regional MBF,16 oxygen, and lactate metabolism were obtained. Next, norepinephrine was infused intravenously to elevate mean arterial pressure to ≈150 mm Hg, and at the same time, heart rate was increased by atrial pacing as required to attain a rate of ≈150 bpm. Once both heart rate and blood pressure were stable, timing was begun, and repeat measurements of all experimental parameters were obtained at 10 and 30 minutes of combined pacing plus norepinephrine stress. After completion of stress measurements, 4 of the animals were killed and their hearts removed and sectioned for determination of microsphere activity (see below). In 5 others (group 1a), the animal was observed for an additional 28 to 115 minutes (median, 47 minutes), at which time a final set of measurements of all experimental parameters was obtained, after which the animal was killed and the heart processed as described below. These animals were given intravenous injections of 30 mCi of 99mTc-labeled BMS 181321 at 14 to 23 minutes (average, 18 minutes) of combined stress to obtain independent biochemical evidence of ischemia in the model.17 18
Group 2 (n=11)
An additional group of animals was instrumented and studied according to the same protocol as described above, except that regional MBF was not measured and 99mTc-labeled BMS 181321 was not used. In these animals, measurements of hemodynamics and arterial and AIV blood gases were made at baseline, every 10 minutes during stress, and every 10 minutes during the 1-hour recovery period after stress was discontinued. Regional contractile function was measured by radionuclide ventriculography in 8 of 11 animals. Radionuclide ventriculograms were obtained with a Picker Dynamo gamma camera and ADAC computer after in vitro labeling of the animal's red blood cells with ≈25 mCi of [99mTc]pertechnitate. Images were acquired at the times noted above in a steep left lateral view, which provides optimal visualization of anterior and inferior walls of the heart.19 Complete data were available from 6 of 8 animals. One animal had ventricular fibrillation and died after completion of baseline measurements. The other died 20 minutes after discontinuation of stress.
Myocardial necrosis was assessed by histology in 10 of 11 animals, by TTC staining in 7 of 11, and by myocardial CK activity in 4 of 11. After the animal was killed, the chest was opened and the position of the stenosis was marked with a suture. Next, the stenosis catheter was carefully withdrawn from the vessel. After this, the heart was removed, and the coronary arteries were perfused via the aorta at constant pressure (100 mm Hg) with ≈1 L of 1% TTC solution at 37°C over 5 to 10 minutes.
Measurements of myocardial CK levels were obtained in 4 of 11 animals described above. In these animals, after an appropriate level of anesthesia was ensured, the chest was opened before the animal was killed. Next, two needle biopsies were obtained from both the stenotic and circumflex perfusion territories. Each sample was immediately frozen in liquid nitrogen for subsequent CK determination (see below). After tissue biopsies had been obtained and the animal killed, the heart was removed. Next, the aortic root was cannulated and the myocardium perfused with TTC as described above.
Postmortem Tissue Processing
Regional MBF and BMS 181321 Activity
Group 1 animals killed immediately after stress (n=4) had stenotic and normal zones identified visually based on (1) previous work performed in this laboratory that used radioactive microspheres to mark the stenotic zone14 15 and (2) current work with Evans blue dye as a marker of the stenotic area (see below). Myocardial specimens from each region were divided into endocardial and epicardial halves (weight range, 1.5 to 3.5 g), digested, and counted for colored microsphere measurements of flow as described by others.16
The hearts of group 1a animals that had been killed ≈50 minutes after stress was discontinued were processed as follows. Identification of myocardium distal to the stenosis was facilitated by a 7F perfusion catheter positioned in the LAD at the level of the stenosis and secured in place with a 3-0 suture. The stenotic zone then was demarcated by perfusion of the myocardium with Evans blue dye at 100 mm Hg for ≈10 minutes.
After completion of the staining procedure, the heart was sliced from apex to base into sections ≈1 cm thick that were oriented normal to the long axis of the left ventricle. The slices were imaged by being placed on the face of a Picker Dynamo gamma camera equipped with a general all-purpose collimator and interfaced with an MDS A3 computer system. Before sectioning, counts also were recorded in one 5×5-pixel ROI placed over the center of the area of greatest tracer uptake in each image and another over the normal zone in the same section. After imaging of intact tissue slices, stained and unstained samples were removed from each section, weighed, and imaged separately to obtain counts per gram in stenotic and normal zones, respectively. Finally, to ensure close correspondence between 99mTc-labeled BMS 181321 data and microsphere blood flow data, the same subsections as used for imaging were later digested and counted for microsphere measurements of blood flow as described above.
Myocardial Gross Pathology and Histology
After completion of TTC staining, hearts were immersed in 10% formalin for 24 to 48 hours. At the end of this time, each was removed, photographed, and then sliced normal to the long axis of the left ventricle into sections ≈0.5 cm thick. Each section was photographed, and the extent of brick red TTC staining was noted. A transmural sample ≈2×2 cm was removed from the perfusion zone distal to the stenosis in the center of the anterior wall of the left ventricle of each section and prepared for microscopic analysis (hematoxylin-eosin stain) according to standard technique.
Myocardial CK Activity
Tissue samples were weighed and then homogenized in isotonic buffer (in mmol/L: Tris-HCl 50, pH 6.8, sucrose 250, magnesium acetate 5, EDTA 0.4, and dithiothreitol 2.5). Next, the homogenate was spun at 14 000g for 5 minutes (4°C). The supernatant was removed and assayed for CK activity by use of spectrophotometric technique and commercially available reagents (Sigma Diagnostics, CPK quantitative, kinetic determination). Values for individual samples (n=2) from each zone were averaged, and results were expressed as IU/g protein.
Regional Myocardial Oxygen and Lactate Consumption
These measurements were made as previously reported.1 15 A Lex-O2-Con machine was used to measure oxygen content in arterial and AIV blood. Regional MV̇o2 was computed as the product of transmural blood flow and the arterial minus AIV oxygen content difference.
Lactate concentration in plasma was determined by a spectrophotometric method using commercially available kits (Calbiochem Rapid Lactate Reagents, Calbiochem-Behring). Regional myocardial lactate consumption was computed as the product of transmural blood flow and the arterial minus AIV lactate concentration difference.
Radionuclide ventriculograms were processed with Fourier analysis and commercially available software (ADAC Laboratories) to obtain amplitude and phase images. Phase images ensured appropriate separation of the left atrium from the left ventricle. Amplitude images provided a quantitative index of volume change (ie, contraction) in each pixel of the left ventricle. To minimize statistical noise, an ROI covering the anterior wall (stenotic zone) and another covering the inferior wall (normal zone) were placed over the baseline ventriculogram, and the average value of amplitude units within the region was used in data analysis. The same region was superimposed on subsequent amplitude images for each study interval. Baseline inferior wall amplitude was set to unity. Both anterior and inferior wall amplitudes then were expressed as fractions (or multiples) of the baseline inferior wall value at each point in the study.
All data are expressed as mean±SD. The significance of differences among group mean values of continuous variables (eg, MBF, metabolic parameters) was assessed by repeated-measures ANOVA. If ANOVA demonstrated a statistically significant F statistic, then a contrast test was used to compare means and assess the significance of differences between them (SuperAnova, Abacus Concepts). Values of P<.05 were considered statistically significant.
Unless otherwise noted, results presented here pertain to group 1 as a whole (n=9). In the case of relevant physiological parameters, a subgroup analysis is presented based on 5 of 9 animals (group 1a) in which poststress measurements were made.
As required by the study protocol, heart rate, mean arterial pressure, and rate-pressure product all increased significantly (P<.01) versus baseline at both 10 and 30 minutes of stress (Table 1⇓). Mean left atrial pressure also tended to increase versus baseline during stress, although the changes failed to attain statistical significance. Identical results were obtained in the subgroup with poststress measurements. In these animals, heart rate, mean arterial pressure, left atrial pressure, and rate-pressure product after stress returned to levels that did not differ significantly from baseline.
Stenotic-zone endocardial flow at baseline was reduced (P<.05) versus that of the normal zone (Table 2a⇓). Epicardial flow distal to the stenosis, however, did not differ significantly from that of the reference region at baseline.
In response to stress, both endocardial and epicardial flows in the normal zone increased significantly (P<.01), as expected, versus baseline. Stenotic-zone endocardial flow during stress was unchanged versus baseline. In contrast, epicardial flow distal to the stenosis increased significantly (P<.01) versus baseline at both 10 and 30 minutes of stress. It should be noted, however, that the maximal increment in stenotic-zone epicardial flow (1.3±0.3 times baseline) was less (P<.01) than that of the normal zone (1.6±0.4 times baseline), even though both started from the same initial level (1.16 mL·min−1·g−1).
For group 1a, normal-zone endocardial and epicardial flows at 50 minutes after stress did not differ significantly from baseline levels. In contrast, after cessation of stress, both endocardial and epicardial flows in the stenotic zone were lower versus baseline (34±23% and 30±20%, respectively; both P<.01).
Regional Myocardial Oxygen and Lactate Metabolism
MV̇o2 in the stenotic zone increased versus baseline at both the 10-minute (P<.01) and 30-minute (P<.05) measurement points (Table 3⇓). The increase occurred primarily as a result of enhanced epicardial blood flow, since myocardial oxygen extraction declined (P<.01) and AIV oxygen content increased (P<.01) versus baseline at both measurement points. Comparison of poststress MV̇o2 with baseline levels was possible in group 1a animals and demonstrated a 28±25% decline (P<.05) that was entirely accounted for by the decline in stenotic-zone blood flow (see above), since myocardial oxygen extraction and AIV oxygen content after stress were unchanged versus baseline in this subset.
AIV pH declined significantly (P<.01) versus baseline at both 10 and 30 minutes of stress. Arterial pH, however, also declined significantly (P<.01) versus baseline during stress. In group 1a, both arterial and AIV pH were reduced (P<.01) versus baseline at the poststress measurement point. The ratio [H+]AIV:[H+]arterial, however, did not change significantly between these times.
Stenotic-zone lactate metabolism in general changed from consumption at baseline (0.16±0.20 mmol·min−1·100 g−1) toward production with stress (0.11±0.30 mmol·min−1·100 g−1 at 10 minutes and −0.04±0.42 mmol·min−1·100 g−1 at 30 minutes). Although the changes failed to attain statistical significance, there was a trend toward more lactate production at 30 minutes of stress (6 of 9 animals were lactate producers). However, the subset with poststress measurements did not demonstrate any significant difference between baseline (0.12±0.20) and poststress (−0.01±0.25) lactate metabolism.
Regional Myocardial 99mTc-Labeled BMS 181321 Activity
In each group 1a animal, the 99mTc-labeled BMS 181321 activity ratio (stenotic:normal zone) in the 5×5-pixel ROI was >1 (mean, 1.9±0.9). The activity ratio in stenotic and normal zones imaged separately, after sectioning based on Evans blue staining, was >1 in 4 of 5 animals (mean, 1.2±0.1). The remaining animal had a stenotic- to normal-zone activity ratio of 0.9.
Group 2: Regional Myocardial Contractile Function
At baseline, anterior wall contraction (0.66±0.12) was reduced (P<.01) versus that of the inferior wall (set to 1; see Fig 1⇓ and Table 4⇓). In response to norepinephrine infusion, inferior wall contraction was unchanged versus baseline. In contrast, anterior wall contraction declined 34±14% (P<.001). Inferior wall contraction was unchanged versus baseline during the recovery period, whereas anterior wall contraction remained depressed (39±13% below baseline; P<.001). Hemodynamic and blood gas data for group 2 are presented in Table 4⇓.
Gross Pathology, Histology, and Myocardial CK Activity
The stenotic zone of each animal stained brick red with TTC, with one exception. In one animal, there was a technical problem with TTC administration such that only the right coronary artery was well perfused (solid brick red). Both the stenotic and left circumflex territories of this animal demonstrated heterogeneous red staining (see below). There was, however, no histological evidence of discrete, focal necrosis within the stenotic zone of this or any of the other animals (Fig 2⇓).
It should be noted that in another animal, a small diagonal branch of the LAD was occluded by the wall of the stenosis at the point at which it lodged within the vessel. In this animal, a small, discrete island of tissue along the lateral wall of the left ventricle was unstained by TTC and demonstrated early, patchy loss of cell architecture and scattered pyknotic nuclei on histological examination. The anterior wall of this animal (ie, stenotic zone) was normal on histological examination and TTC stain.
CK activity (Table 5⇓) of the stenotic zone (554±266 IU/g) did not differ significantly from that of the normal zone (417±157 IU/g). Furthermore, for each animal, the average CK value of stenotic-zone samples either equaled (n=1) or exceeded (n=3) that of the normal zone. The one animal mentioned above with heterogeneous TTC staining of the stenotic zone (Table 5⇓, animal 1) had CK activity (673 IU/g) that exceeded that of the circumflex territory (374 IU/g) and was comparable to those of the other three animals with homogeneous red stain of the stenotic zone.
This study tested the hypotheses that (1) the myocardium may adapt rather than exhibit evidence of progressive metabolic deterioration and necrosis in response to prolonged demand-induced ischemia and (2) after stress, moderate residual dysfunction (versus baseline) with proportionate reduction in MBF and oxygen consumption consistent with myocardial hibernation may persist for some time. The data obtained support both hypotheses. Thus, MV̇o2 by the stenotic zone actually increased at 10 minutes of stress and remained elevated at 30 minutes of stress. Increased MV̇o2 during stress in the present study most likely reflects the combination of catecholamine-induced oxygen “wasting”20 21 and increased mobilization and delivery of free fatty acids22 to the myocardium. In addition, the fact that both MV̇o2 and AIV pH were unchanged between 10 and 30 minutes of stress in group 1 argues against progressive metabolic deterioration in the model, notwithstanding the trend toward more lactate production at 30 minutes of stress. Furthermore, AIV pH at 30 minutes of stress in group 1 was unchanged versus 10 minutes of stress despite the decline in arterial pH.
One hour after discontinuation of stress, both stenotic-zone blood flow and MV̇o2 were reduced ≈30% versus baseline (ie, prestress) levels. It is important to emphasize that the degree of residual reduction in stenotic-zone blood flow and oxygen consumption very closely matched the extent of residual impairment of stenotic-zone contractile function, which also was reduced ≈35% versus baseline. Whether this new steady state represents myocardial hibernation or stunning superimposed on hibernation depends on how these terms are defined.6 23 24 It was demonstrated in the present study that in the stenotic zone, endocardial flow was reduced versus the normal zone at baseline and did not change in response to stress and that baseline epicardial flow was equal to that of the normal zone and increased in response to stress, albeit to a lesser extent. Furthermore, 50 minutes after discontinuation of stress, flow in both layers of the stenotic zone was reduced versus respective baseline levels, even though heart rate and arterial pressure had returned to control levels. Data from prior studies (see References 1, 14, and 25 and Fig 3⇓) and results of radionuclide ventriculography presented in the present study (Fig 1⇑) clearly indicate that regional dysfunction was present at baseline, worsened with stress, and remained depressed versus baseline after discontinuation of stress. Accordingly, in the endocardium, subacute hibernation was present at baseline and, in conjunction with the radionuclide ventriculograms, confirms results of earlier work that demonstrate that impaired endocardial perfusion and function may compromise function across the entire left ventricular wall.26
Myocardial dysfunction in the poststress period could be called stunning superimposed on hibernation if one allows the definition of stunning to include residual functional impairment after demand-induced ischemia. However, because stunning classically follows an absolute reduction in MBF with coronary artery occlusion11 and is associated with return to baseline level of MV̇o2 (ie, oxygen consumption out of proportion to the level of residual contractile function that is impaired), it is more appropriate to consider the steady state observed in recovery in the present study as one of hibernation. This is so because the recovery period was characterized by a balanced reduction (≈30% to 35% below baseline) in blood flow, oxygen consumption, and contractile function. Detailed flow, function, and metabolism measurements at regular intervals for hours or possibly even days after stress would be helpful in determining the extent to which the increment in contractile dysfunction related to demand-induced ischemia is reversible.
It is important to emphasize that reduced MV̇o2 ≈50 minutes after discontinuation of stress in fact is related to prolonged stress and does not reflect spontaneous, time-dependent deterioration of the animal preparation. Two lines of evidence support this conclusion. First, in a prior study from this laboratory,1 we demonstrated that regional MBF, oxygen consumption, and contraction declined abruptly after placement of an 80% stenosis in the LAD, then stabilized after 30 to 40 minutes at a level that remained unchanged over 2 hours of observation (Fig 3⇑). Contractile function and MBF in the circumflex zone remained stable without any evidence of deterioration during the 2- to 3-hour observation period. Second, in the present investigation, hemodynamics as well as normal-zone blood flow and contractile function returned to baseline levels at ≈50 to 60 minutes after stress, observations that argue strongly against spontaneous, time-dependent deterioration of the animal preparation.
Reduced MV̇o2 of ≈30% after stress cannot be explained as the result of a mixture of tissue, 70% of which had baseline level of MV̇o2 (ie, 10 mL·min−1·100 g−1) and 30% of which had MV̇o2 of 0 mL·min−1·100 g−1 (ie, was infarcted by stress). Although such a mixture could account for the observed level of MV̇o2 after stress (ie, 7 mL·min−1·100 g−1), it is unlikely to account for the observed level of myocardial oxygen extraction (83%), which was unchanged versus baseline (85%). Furthermore, histological (Fig 2⇑) and myocardial CK data (Table 5⇑) in group 2 animals specifically excluded necrosis in the stenotic zone.
In vitro measurement of 99mTc-labeled BMS 181321 activity confirmed the presence of myocardial ischemia in the model in all group 1a animals. The one animal in which the activity ratio was <1 in sectioned slices actually had evidence of increased uptake in the stenotic region in the slice images before sectioning (stenotic- to normal-zone activity ratio, 1.1). It is possible, therefore, that the final ratio of 0.9 derived from tissue that had been cut into stained and unstained portions reflects the fact that some of the Evans blue–stained tissue bordered the ischemic core and thus contributed weight but relatively fewer counts to the final measurement. The same reasoning also would explain why the stenotic- to normal-zone activity ratio determined from separately imaged zones (1.2±0.1) was less than that determined with the 5×5-pixel ROI (1.9±0.9). Each of the group 1 animals in which 99mTc-labeled BMS 181321 was not injected demonstrated lactate production at the 30-minute measurement point. Accordingly, the data obtained in the present study confirm metabolic evidence of ischemia in the stenotic region.
Two issues concerning the animal model used for this study also should be considered. First, selectivity of AIV blood samples for myocardium perfused by the LAD has been documented by prior experiments from this laboratory27 and provides strong support for the validity of conclusions that depend on metabolic measurements obtained from these samples. Second, as noted above, the effect of stenosis placement on regional contractile function and the stability of normal-zone contractile function have been documented over a 2- to 3-hour period.1 Accordingly, it is clear, as shown in Fig 3⇑, that the stress intervention in the present study was begun on a stable baseline of regional dysfunction and that the normal circumflex zone provides a suitable reference area whose blood flow and function do not deteriorate over at least a 2- to 3-hour observation period. Thus, the hypothesis that norepinephrine infusion per se could have altered segmental function by homologous desensitization is refuted by the fact that, in the present study, normal-zone contractile function did not differ significantly from baseline during or after norepinephrine administration.
In the setting of a severe coronary arterial stenosis with reduced baseline endocardial blood flow indicative of subacute hibernation, demand-induced myocardial ischemia can be prolonged for at least 30 minutes without causing progressive deterioration in indexes of myocardial aerobic metabolism, oxygen consumption, or segmental systolic function. Nor does prolonged (30-minute) stress necessarily progress to necrosis. Indeed, it would appear that, as long as MBF is maintained at or above baseline levels, a new steady state develops, characterized by a constant level of myocardial ischemia. The duration beyond 30 minutes for which such an equilibrium can be maintained cannot be stated from the results of this study.
One hour after relief of prolonged stress, regional MV̇o2, contractile function, and blood flow all are reduced (≈30% to 35%) versus baseline. Since a balanced reduction in each of these parameters is present, the new steady state is best characterized as one of myocardial hibernation that was deepened (hibernation was present in endocardium at baseline) by demand-induced ischemia. Additional studies with a chronic stenosis model in which serial measurements of regional MBF, metabolism, and function are made over a period of hours to days will be required to determine whether this state persists or is reversible with time. Future experiments also will be needed to test the hypothesis that baseline hibernation has a protective effect in terms of permitting steady-state ischemia during prolonged stress and blocking progression to necrosis.
This study was supported in part by a grant from Bristol Myers Squibb Pharmaceutical Research Institute, New Brunswick, NJ. We gratefully acknowledge the skilled technical assistance of the following individuals: Tammy Donohue, Pat Mastrofrancesco, and Lorraine Schofield of Rhode Island Hospital and J. Luis Guerrero, Tracey Svizzero, and Robert Wilkinson of Massachusetts General Hospital. Edie Sinagra helped in preparation of the manuscript.
Selected Abbreviations and Acronyms
|AIV||=||anterior interventricular vein|
|LAD||=||left anterior descending coronary artery|
|MBF||=||myocardial blood flow|
|MV̇o2||=||myocardial oxygen consumption|
|ROI||=||region of interest|
- Received January 31, 1996.
- Revision received February 8, 1996.
- Accepted February 16, 1996.
- Copyright © 1996 by American Heart Association
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