(Circulation. 1996;94:1430-1440.)
© 1996 American Heart Association, Inc.
Articles |
Contractile Versus Microvascular Reserve for the Determination of the Extent of Myocardial Salvage After Reperfusion
The Effect of Residual Coronary Stenosis
the Cardiovascular Division, University of Virginia, Charlottesville.
Correspondence to Sanjiv Kaul, MD, Cardiovascular Division, Box 158, University of Virginia Medical Center, Charlottesville, VA 22908. E-mail sk@virginia.edu.
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Abstract |
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Background We hypothesized that microvascular reserve is a better indicator of the extent of viable myocardium postinfarction than contractile reserve, especially in the presence of a residual stenosis of the infarct-related artery.
Methods and Results Fifteen dogs with various infarct sizes were studied after reperfusion. Contractile reserve, studied by use of dobutamine echocardiography, and microvascular reserve, studied by use of myocardial contrast echocardiography, were measured both before and after creation of a stenosis. In the absence of a stenosis, the relation between infarct size, expressed as percent of risk area, and wall thickening improved with increasing doses of dobutamine (r=.41, .71, and .90 for 5, 10, and 15 µg·kg-1·min-1, respectively; P<.01 for dobutamine 15 µg·kg-1·min-1). In the presence of a stenosis, however, the relation was poor for all doses of dobutamine (r=.22, .57, and .32 for 5, 10, and 15 µg·kg-1·min-1, respectively; P<.01 for 15 µg·kg-1·min-1 dobutamine in the absence of a stenosis). There was a fair correlation between infarct size and perfusion defect size on myocardial contrast echocardiography after reperfusion (r=.82), with the defect size underestimating infarct size by approximately 20%. This relationship improved (P<.01) during infusions of both adenosine (r=.99) and dobutamine (r=.94) in the absence of a stenosis. The correlations between infarct size and perfusion defect on myocardial contrast echocardiography also remained good in the presence of a stenosis (r=.95 and .81 for adenosine and dobutamine, respectively; P=NS compared with stenosis).
Conclusions Microvascular reserve is superior to contractile reserve for definition of the spatial topography of necrosis and hence the extent of viable myocardium within the infarct bed after reperfusion, particularly when a residual stenosis is present in the infarct-related artery.
Key Words: myocardium • stenosis • infarction • echocardiography
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Because of postischemic dysfunction, the degree of wall thickening immediately after reperfusion does not indicate the extent of myocardium that has undergone necrosis.1 2 In the absence of significant necrosis and flow limitation, however, spontaneous recovery of function within the infarct zone usually occurs within days to weeks after reperfusion.2 3 4 5 6 Because the endocardial half of the LV wall is the major contributor to wall thickening,7 8 9 regional function may not improve if a substantial portion of the endocardium is necrosed despite salvage of the remaining myocardium and establishment of adequate flow to that area. In such a situation, even serial assessment of regional function may be insufficient to determine the extent of myocardial salvage after reperfusion.
Both dobutamine echocardiography and MCE have been used to assess the presence and extent of viable myocardium after reperfusion.10 11 12 13 14 15 16 17 18 The basis for the use of dobutamine echocardiography is its ability to elicit contractile reserve in the postischemic viable myocardium.19 20 21 22 The basis for the use of MCE is its ability to delineate microvascular injury in necrotic areas from normal microvasculature in viable areas within the infarct bed.23 24 25 26 The presence of a residual stenosis in the infarct-related artery may attenuate the contractile reserve when dobutamine is used.27 On the other hand, the absence of such a stenosis may mask the extent of microvascular damage assessed by MCE because of reactive hyperemia in regions of irreversibly injured myocardium.24
We hypothesized that microvascular reserve is a better indicator of the extent of myocardial viability in the postischemic myocardium than the presence of contractile reserve, especially when a residual stenosis of the infarct-related artery is present. To test this hypothesis, we studied an open-chest canine model of coronary occlusion and reperfusion before and after placement of a stenosis on the infarct-related artery.
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Animal Preparation
The protocol conformed to the American Heart Association guidelines for animal research use and was approved by the Animal Research Committee at the University of Virginia. Fifteen mongrel dogs (weight, 27±2 kg [mean±SD]) were used for the experiment. They were anesthetized with 30 mg/kg of sodium pentobarbital (Abbott Laboratories), intubated, and mechanically ventilated by use of a respirator pump (Harvard Apparatus, Model 607). A 7F polyethylene catheter was placed in each femoral artery for duplicate reference-sample withdrawal during radiolabeled microsphere injection, and one of these catheters was also used for arterial pressure monitoring. A femoral vein was cannulated with a 7F catheter for intravenous administration of fluid and drugs. Additional anesthesia was administered during the experiment as needed.
A left lateral thoracotomy was performed, and the heart was suspended in a pericardial cradle. A 7F pigtail catheter was inserted into the left carotid artery, and its tip was positioned in the proximal aortic root. It was connected to a power injector (model 3000, Liebel-Flarsheim) for the injection of microbubbles. A 7F catheter was placed in the left atrium for measurement of mean left atrial pressure and for injection of radiolabeled microspheres. The arterial and left atrial pressure catheters were attached to fluid-filled transducers, which in turn were connected to a multichannel recorder (model ES2000, Gould Electronics). The proximal or middle portion of either the left anterior descending or LCx coronary artery was dissected free from surrounding tissue, and a custom-designed reversible snare was placed loosely around it. A 2-mm ultrasonic time-of-flight flow probe (series SB, Transonics) was placed proximal to the snare and was connected to a digital flowmeter (model T206, Transonics) to monitor flow in the vessel.
Acquisition of Echocardiographic Data
Echocardiographic data were acquired with use of a phased array system (RT5000, General Electric Medical Systems) equipped with a 5-MHz transducer. The gain settings were optimized at the beginning of the experiment and held constant throughout. A maximum dynamic range of 72 dB was used. A saline bath acted as an acoustic interface between the heart and transducer. Imaging was performed at the short-axis mid-papillary muscle level, and the data were recorded on 1.25-cm VHS videotape with a video recorder (Panasonic model AG6200, Matsushita Electrical Co).
Sonicated albumin microbubbles with a mean size of 4.3 µm and concentration of 0.5 billion bubbles/mL (Albunex, Molecular Biosystems Inc) were used for MCE. At the doses used in this study, it has been shown that this agent does not significantly alter systemic or coronary hemodynamics.28 29 These microbubbles were power injected into the aortic root during simultaneous echocardiographic imaging. Although the dose of microbubbles required for optimal myocardial opacification (1 to 5 mL) varied between dogs, the same dose was used for every stage in each dog.
Analysis of Echocardiographic Data
Our approach to the off-line analysis of MCE images has been described previously.30 These images were transferred from videotape to the image memory of an off-line computer system (Mipron, Kontron) in a 244x244x8-bit format. A single contrast-enhanced end-diastolic frame that depicted the maximum disparity in contrast enhancement between the left anterior descending and LCx coronary arterial beds was aligned with a precontrast end-diastolic frame by use of computer cross correlation.31 The precontrast frame was digitally subtracted from the contrast-enhanced frame, and the video intensity scale in the resulting subtracted frame was expanded to a dynamic range of 128 gray levels, whereby the pixel with the greatest contrast change was assigned a level of 128 and all others were assigned proportionally lower values. Each pixel was assigned a color on the basis of the degree of contrast enhancement, whereby shades of red, progressing to hues of orange, yellow, and white, represented incremental contrast opacification. Areas that demonstrated no increase in video intensity were not assigned a color.30 Contrast defects during coronary occlusion and reperfusion were planimetered and expressed as a percent of the LV short-axis slice.
Our method of quantifying regional wall thickening has also been described in detail elsewhere.32 In brief, several consecutive cardiac cycles were digitized into the memory of the off-line computer system. A representative contraction sequence from end diastole to end systole (defined as the largest and smallest LV chamber sizes in the cardiac cycle, respectively) was identified, and all frames in the sequence were analyzed for regional wall thickening. In each frame, 8 to 12 points were placed on the epicardium and endocardium, respectively, in which these regions could be defined clearly. These points were automatically connected by use of cubic spline interpolation33 to define the epicardial and endocardial outlines, respectively. The observer could change portions of the outlines if they did not agree with those drawn by the computer while the images and their accompanying overlays were viewed in cine loop.
Wall thickness was measured automatically in each frame as the shortest distance between the epicardium and endocardium along 100 chords placed equidistant along the circumference of the heart by the computer. To correct for cardiac rotation, the chord at the junction of the right ventricular free wall and LV posterior wall (defined by the operator) was used as a reference point in each frame. The maximal thickening or thinning of the LV wall in the entire systolic contraction sequence was then defined for each chord by the computer. These values for chords present within the central 75% of the risk area were then averaged. A plastic overlay defined the risk area from MCE images during coronary occlusion.
Infarct Size Determination
At the conclusion of the experiment, the heart was excised and sectioned into 1-cm-thick short-axis slices. The slice that corresponded to the echocardiographic imaging plane was immersed in a solution of 1.3% TTC (Sigma Chemical Co) and 0.2 mol/L Sorensen's buffer (KH2PO4 and K2HPO4 in distilled water, pH 7.4) at 37° for 20 minutes, followed by fixation in 10% formalin. This technique stains viable myocardium brick red.34 An image of the short-axis slice was acquired into the off-line computer system by use of a high-resolution video camera (66 series, Date-MTI Corp). Infarct size was measured by planimetry of the unstained portions of the digitized image. For comparison with wall thickening, infarct size was expressed as a percent of the risk area, whereas for comparison with MCE perfusion defect size, it was expressed as a percent of the LV short-axis area.
Measurement of Myocardial Blood Flow
Regional myocardial blood flow was measured by use of radiolabeled microspheres.35 For each stage, approximately 2x106 10-µm microspheres (DuPont Medical Products) suspended in 4 mL of 0.01% Tween 80 were injected into the left atrium during simultaneous 90-second reference-sample withdrawals from both femoral arteries by use of a timed withdrawal pump (model 944, Harvard Apparatus). Postmortem, the LV short-axis slice that corresponded to the MCE image was sectioned into 16 wedge-shaped segments, and each piece was further cut into epicardial, midwall, and endocardial thirds. The myocardial and arterial reference samples were counted in a gamma-well scintillation counter (model 1282, LKB Wallac) and corrections for spillover of radioactivity into neighboring windows were made by use of a custom-designed computer program.36 Flow to each sample was calculated by use of the equation Qm=(CmxQr)/Cr, where Qm is myocardial flow (mL/min), Cm is tissue counts (cpm/g), Qr is rate of arterial sample withdrawal, and Cr is counts in the arterial reference sample (cpm/g). Transmural blood flow (mL·min-1·g-1) was calculated as the quotient of the summed flows to the individual pieces and their combined weight. Blood flow to the central two thirds of the risk area (thus excluding lateral borders with intermediate levels of flow) was normalized to flow in the nonischemic bed.
Experimental Protocol
After hemodynamic and echocardiographic data were acquired at baseline, the left anterior descending (8 dogs) or LCx coronary artery (7 dogs) was occluded for 3 to 6 hours to produce infarcts of different sizes. Toward the end of the occlusion period, wall thickening and risk area were measured. The occlusion was then released; 15 minutes later, radiolabeled microspheres were injected to measure myocardial blood flow, and echocardiographic data were acquired for wall thickening and MCE perfusion defects. An intravenous infusion of adenosine (0.2 mg·kg-1·min-1) was initiated, and when the increase of flow in the coronary artery had reached a plateau, MCE and microsphere injection were repeated. The drug was then discontinued. Dobutamine infusion was started at a dose of 5 µg·kg-1·min-1 and subsequently increased to 10 and 15 µg·kg-1·min-1 at 5-minute intervals for each dose. Wall-thickening data were acquired after 3 minutes of each dose. At the dose of 15 µg·kg-1·min-1, microspheres were injected for the measurement of myocardial blood flow, and MCE was performed to define perfusion defects. The drug was discontinued, and a stenosis was placed over the infarct-related artery to produce variable attenuation (mild to severe in individual dogs) of the hyperemic response elicited by a 20-second occlusion of the artery. After placement of the stenosis, the adenosine and dobutamine stages of the protocol were repeated. The drugs were given in random order both at baseline and during stenosis placement, with a 15-minute interval between them to allow for systemic hemodynamics and coronary blood flow within the noninfarct-related artery to return to baseline.
Statistical Methods
Correlations between wall thickening and MCE perfusion defects versus infarct size were made by use of linear regression analysis. Slopes and intercepts of different regression lines were compared by use of Student's t test. When more than one comparison was performed, the Bonferroni correction for multiple comparisons was used. Comparisons of myocardial blood flow and infarct size between different stages were made by use of repeated measures ANOVA. Statistical significance was defined as a value of P<.05 (two-sided).
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Wall-thickening data at baseline, during coronary occlusion and reflow, and for each of the 3 doses of dobutamine before placement of stenosis were acquired in all 15 dogs (total of 90 stages). After placement of a stenosis, wall-thickening data during dobutamine infusion were available for only 37 of the 45 stages because of ventricular fibrillation in 3 dogs that required defibrillation, after which wall thickening became abnormal and was not analyzed. Similarly, although adequate MCE data were acquired at baseline and during coronary occlusion in all dogs, they could be acquired after reflow for only 57 of the 75 possible stages. Two dogs died of ventricular fibrillation, and 1 had severe hypotension after adenosine infusion from which it could not be resuscitated. The images had artifacts from the saline bath in 6 stages. Radiolabeled microsphere data were available for analysis in 61 stages in the 14 dogs in whom they were injected. The risk area was 29±11% of the LV short axis.
Contractile Reserve
Table 1
depicts the hemodynamic data during dobutamine infusion. Left atrial pressure remained more or less constant during all stages. The heart rate after reflow was significantly lower than that during any dose of dobutamine. Although heart rate and diastolic and systolic blood pressures were higher at greater doses of dobutamine, the interdose differences were not significant. Similarly, although diastolic and systolic blood pressures were lower for the same dose of dobutamine in the presence versus absence of stenosis, these differences were not significant. The double product was, however, significantly higher at 10 and 15 µg·kg-1·min-1 of dobutamine in the absence versus presence of stenosis.
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Wall-thickening data are depicted in Table 2. Although wall thickening in the control bed increased with increasing doses of dobutamine, the interdose differences were not significant. Wall thickening in the control bed was not affected by the presence of a stenosis in the infarct-related artery, whereas in the infarct bed, it was significantly higher before coronary occlusion than in all other subsequent stages. Wall thinning was noted during coronary occlusion, severe reduction in thickening was seen during reflow, and the increase in wall thickening was attenuated at each dose of dobutamine in the presence versus absence of stenosis. This disparity was most marked at the dose of 15 µg·kg-1·min-1.
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Fig 1A depicts the poor relationship between infarct size, expressed as a percent of the risk area (x axis), and wall thickening (y axis) at 15 minutes after reflow in the absence of any drug. Figs 2, 3, and 4 illustrate the relationship between infarct size, expressed as a percent of the risk area (x axis), and percent wall thickening (y axis) in the absence of a stenosis during dobutamine (5, 10, and 15 µg·kg-1·min-1, respectively). The relationship improved with higher doses of dobutamine and was best at a dose of 15 µg·kg-1·min-1 (slope and intercept were P<.01 compared with no dobutamine and dobutamine at 5 and 10 µg·kg-1·min-1). These figures also depict the relationship between infarct size, expressed as a percent of the risk area (x axis), and wall thickening (y axis) in the presence of a stenosis during the three different doses of dobutamine. It is apparent that at all doses of dobutamine, the relationship between infarct size and wall thickening was worse in the presence than in the absence of stenosis. This difference reached statistical significance (P<.01 for both intercept and slope) at a dose of 15 µg·kg-1·min-1. In the presence of a stenosis, some small infarcts demonstrated improved thickening at low doses of dobutamine but worsened at higher doses.
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Microvascular Reserve
Table 3 depicts blood flow data during reflow as well as during adenosine and dobutamine infusions, both in the absence and presence of stenosis. Because of reactive hyperemia, transmural flow within the infarct zone was similar to that in the control bed. Whereas epicardial flows were also similar in the two beds, endocardial flow was reduced in the infarct bed because of the no-reflow or low-reflow phenomenon. As a result, perfusion defects were apparent in the infarct bed on MCE after reflow even in the absence of pharmacological agents. Fig 1B
depicts the relationship between infarct size (x axis) and MCE perfusion defect (y axis) during reflow, expressed as a percent of the LV short-axis slice. Although the perfusion defects underestimate infarct size by approximately 20%, their relationship with infarct size is closer (P<.01 for slope and P<.05 for intercept) than that of wall thickening despite considerable scatter (Fig 1A).
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In the presence of pharmacological vasodilation, the abnormal reserve present in the infarct zone is unmasked. As can be seen in Table 3, when adenosine was infused in the absence of a stenosis, the transmural flow increased significantly more in the control bed, which had normal microvascular reserve, than in the infarct bed. The increase in flow to the infarct bed was mostly due to the increase in flow to the epicardial zones that escaped necrosis. When transmural flow in the infarct bed was normalized to that in the control bed, it was significantly lower during infusion of adenosine (60% during versus 115% before infusion). This additional disparity in relative flow during adenosine infusion resulted in larger perfusion defects (18±11% versus 14±11% of the LV short-axis slice during versus before adenosine; P<.001) that more closely approximated infarct size (18±13% of the LV short axis). Fig 5 illustrates an example of perfusion defects in the LCx bed after reflow before (Fig 5A) and after (Fig 5B) infusion of adenosine. It can be appreciated that the perfusion defect size was larger in the presence (Fig 5B) than in the absence of adenosine (Fig 5A) and more closely approximated TTC-determined infarct size (Fig 5C). Fig 6 depicts the relation between infarct size (x axis) and MCE perfusion defect size (y axis), expressed as a percent of the LV short-axis slice, during adenosine infusion in the presence and absence of stenosis. Both slopes and intercepts of the relations are statistically different (P<.01); perfusion defect size as determined by MCE represented a mild overestimation of infarct size.
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Somewhat similar results pertain to the estimation of infarct size by MCE perfusion defects in the presence of dobutamine. The hyperemia in the control bed in the absence of stenosis at 15 µg·kg-1·min-1 of dobutamine was comparable to that at 0.2 mg·kg-1·min-1 of adenosine (Table 3). Consequently, as in the case of adenosine, transmural flow to the infarct bed relative to the control bed was reduced during dobutamine infusion (75% of control bed during infusion versus 115% before infusion). As a result, the perfusion defects were larger during infusion of dobutamine compared with before its infusion (15±13% versus 13±9% of the LV short-axis slice, P<.01). As shown in Fig 7, there was a close linear relation between infarct size and MCE perfusion defect size during dobutamine infusion.
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Fig 8 illustrates MCE perfusion defects after reflow (Fig 8A) and during dobutamine infusion in the absence (Fig 8B) and presence (Fig 8C) of a stenosis in the same dog whose MCE images during adenosine infusion are depicted in Fig 5. The perfusion defect was larger during (Fig 8B) versus before dobutamine infusion (Fig 8A) and closely mimicked infarct size (Fig 8D). In the presence of a stenosis, the defect appeared even denser and larger (Fig 8C) and mildly overestimated infarct size (Fig 8D). Although the epicardial rim was seen clearly, it had more hues of red than yellow and orange, as seen in the control bed.
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For the entire group of dogs that received dobutamine, the MCE defect size was 15±13% and 23±11% of the LV short-axis slice before and after the placement of stenosis, respectively. The placement of a stenosis overestimated (P=.04) TTC infarct size, which was 16±11% of the LV short-axis slice in these dogs. Although epicardial flow was less in the infarct compared with the control bed after placement of a stenosis (53% versus 92% of control; P=.02; Table 3), as seen in Fig 8, there was enough perfusion to cause its visualization in the epicardial rim. Fig 7 depicts the relation between infarct and MCE perfusion defect size, expressed as a percent of the LV short-axis slice, during dobutamine infusion in the presence of a stenosis. The relation between MCE perfusion defect and infarct size was statistically different during dobutamine infusion in the presence versus absence of a stenosis (slope was P<.05 and intercept was P<.01). Unlike in the absence of a stenosis, MCE perfusion defects in the presence of a stenosis overestimated the size of smaller infarcts during dobutamine infusion. This occurred because of a greater disparity in transmural flow between the infarct and control beds during dobutamine infusion in the presence versus absence of a stenosis (45% versus 74%; P=.005; Table 3). Interestingly, creation of a stenosis during adenosine infusion produced less of an effect on the MCE defect size than that during dobutamine infusion. As seen in Fig 6, there was only a slight overestimation of infarct size by MCE during adenosine infusion in the presence of a stenosis. The mean MCE defect size increased from 17±12% to 22±10% (P<.001) after the placement of a stenosis. Most of this increase was due to a decrease in epicardial flow, because transmural flow to the infarct compared with the control bed remained unchanged after the placement of a stenosis.
Fig 9 illustrates the relation between the magnitude of transmural flow in the infarct bed normalized to that in the control bed (x axis) and MCE perfusion defect size (y axis) during different stages in which both perfusion defects and blood flows were measured. It is apparent that the MCE perfusion defect size portrays the magnitude of relative flow abnormalities in the infarct bed. The relation between the two was not as good during reflow in the absence of a pharmacological agent (r=.52) and was best during adenosine infusion in the absence of a stenosis (r=.82 and P<.01 compared with reflow in the absence of pharmacological agents). These data indicate that MCE perfusion defects reflect abnormal microvascular reserve better than they do basal flow immediately after reperfusion, when reactive hyperemia may still be present.
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Discussion |
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The new information from our study is that after reperfusion, contractile and microvascular reserve are comparable in defining the extent of viable myocardium within the infarct bed in the absence of residual coronary stenosis. Whereas contractile reserve in this setting provides an indirect assessment of the extent of viable myocardium, the spatial abnormalities in microvascular reserve delineate the topography of the infarct, thus providing a more direct assessment of infarct size and hence the extent of viable myocardium. In the presence of a residual coronary stenosis, the degree of contractile reserve is attenuated depending on the severity of stenosis and does not reflect the extent of viable myocardium. In comparison, despite the presence of a residual stenosis, the spatial distribution of abnormal microvascular reserve still predicts the size of infarction, albeit with a modest overestimation, particularly when the infarct is small. The results of this study, therefore, indicate that MCE may be superior to dobutamine echocardiography to determine the extent of viability in the infarcted myocardium that has undergone successful reperfusion, particularly when a residual stenosis is present in the infarct-related artery.
Contractile Reserve
Whereas the postischemic myocardium is characterized by impairment in regional myocardial thickening at rest, contractile function improves in response to various pharmacological agents, including dobutamine.19 20 21 22 Most experimental studies19 20 21 22 that have used this response to detect viable myocardium have utilized models of pure postischemic dysfunction without any coexisting myocardial necrosis. In the clinical setting, however, such a situation is rare; after successful reflow, various amounts of necrosis are present within the reperfused infarct bed.
The results of the present study support our previous observation in the postinfarction, reperfused myocardium21 that the degree of contractile reserve provides a good assessment of the amount of viable myocardium if there is no residual stenosis to limit hyperemic flow. We postulated that if myocardial blood flow could not increase commensurate with the catecholamine-induced increase in myocardial oxygen consumption, wall thickening would not increase by the expected amount. This postulate implies that depending on the severity of the stenosis, various degrees of attenuation of the contractile response would be seen at different doses of dobutamine, causing an inconsistent relationship between infarct size and wall thickening.
Our results support our hypothesis and the observations of others27 that the increase in myocardial thickening with dobutamine is attenuated in the presence of a coronary stenosis of sufficient severity to partially or completely exhaust coronary flow reserve. Thus, although the presence of viability may be detected when there is a residual stenosis on the basis of an increase in myocardial thickening at a low dose of dobutamine, the amount of viability cannot be quantified on the basis of the degree of thickening. It is obvious, however, that if the myocardium responds to a low dose of dobutamine, the infarct is probably small and located in the endocardium. Not surprisingly, therefore, the response of the myocardium to low doses of dobutamine is highly predictive of spontaneous recovery in regional function,12 because patients with small endocardial infarcts are the ones most likely to show recovery of resting regional function after reperfusion.10 11 12 13 These could be reasons why dobutamine echocardiography has been found to be useful in defining the presence of viable myocardium in postinfarction patients in many studies.
Microvascular Reserve
The present study confirms our previous observations24 that the spatial distribution of abnormal microvascular reserve within the infarct bed immediately after reperfusion defines the topography of infarction in the absence of a residual coronary stenosis. As we previously reported,24 because reactive hyperemia is present for several hours after reflow, unmasking abnormal microvascular reserve rather than simply depicting abnormal flow14 37 forms the cornerstone of the use of MCE to determine infarct size. The no-reflow or low-reflow phenomenon occurs in the center of the infarct zone and is surrounded by vessels in which flow is normal or even increased because microvascular damage is not uniform across the infarct bed. The zones of no reflow or low reflow are identifiable on MCE as areas with very little contrast enhancement. Areas within the infarction that do not show abnormal flow at rest nevertheless have microvascular injury that manifests as abnormal flow reserve, which can be expressed by use of coronary vasodilators. The entire zone of microvascular injury (no flow, low flow, or abnormal flow reserve) is located within the borders of irreversibly injured myocardium. Thus, because it defines abnormal microvascular function after reflow, MCE can be used to define infarct size and hence the extent of myocellular viability.23 24 25 26
The new information in the present study relates to the influence of a residual coronary stenosis on the MCE results, which indicates that placement of a stenosis during reactive hyperemia can result in mild overestimation of infarct size, especially when the infarct is small. In the presence of a stenosis, defects of up to 10% of the LV short-axis slice can be seen even without infarction. In the presence of a stenosis, a transmural flow abnormality is expected during adenosine infusion even in the absence of infarction.38 The presence of a stenosis would then be expected to result in no correlation between MCE perfusion defect and infarct size because the perfusion defect would reflect the risk area rather than the infarct size. We did not observe this effect, probably because of extreme disparities in flow reserve present within different regions of the infarct zone that were not affected by the presence of a stenosis. As depicted in Fig 8, although placement of a stenosis resulted in a decrease in video intensity within the viable epicardial rim compared with the normal bed (Fig 8D), it also resulted in a further decrease in video intensity in the inner layers of the myocardium. Because the imaging algorithm we used depicts relative flow, the necrotic area could still be clearly separated from viable myocardium by use of MCE despite the presence of a stenosis. This also explains the occurrence of small perfusion defects when vasodilators are given in the presence of a stenosis even when there is no infarction. The stenosis results in an overall decrease in intensities within the entire bed, but the postischemic endocardial regions that may have microvascular abnormalities39 too subtle to be seen in the absence of a stenosis become manifest when a severe stenosis is present. The microsphere flow data also support this explanation.
Our results also indicate that in the absence of a stenosis, MCE perfusion defect size reflects infarct size irrespective of the means used to unmask abnormal microvascular reserve. We used adenosine to unmask flow reserve on the basis of its direct effect on the coronary microvessels. Hyperemia induced indirectly by catecholamines via an increased myocardial oxygen demand also produced similar results. Obviously, hyperemia induced by catecholamines is secondary to their effects on cardiac contractility and heart rate. In the present study, high heart rates were obtained with dobutamine at a dose of 15 µg·kg-1·min-1. In patients, this dose may not be adequate, and the effect of ß-blockers must also be taken into consideration. One advantage of a direct coronary vasodilator is that adequate hyperemia can be produced independently of its effects on cardiac function. Furthermore, the present study suggests that in the presence of a stenosis, adenosine may define infarct size better than dobutamine.
Critique of Methods
Previous investigators have demonstrated significant spatial and temporal heterogeneity in regional function,40 especially in ischemic41 and postischemic myocardium.42 Thus, measurement of wall thickening by use of only end-diastolic and end-systolic frames can underestimate the degree of regional dysfunction.41 42 43 We therefore used a semiautomated method that utilizes the entire systolic contraction sequence to determine myocardial thickening.32 With the use of this approach, the maximal degree of dysfunction can be measured whenever it occurs in the cardiac cycle.
Our image-processing algorithm utilizes color coding to optimize delineation of perfusion bed borders.31 This algorithm relies on relative differences in peak video intensity as a marker of differences in blood flow. Therefore, measurement of defects is based on a subjective assessment of the relative differences in intensity, which may result in defining regions as abnormal that may not be abnormal and may also cause difficulties in separating true defects from artifacts. We had to exclude analyses from six stages because of artifacts created by the saline bath.
It would have been useful to have MCE and microsphere data after reflow in the presence of a stenosis without pharmacological agents. These data would have shown whether MCE during attenuation of reactive hyperemia caused by a stenosis predicts infarct size accurately without a concomitant pharmacological intervention. We were, however, limited by the number of microspheres we could use. Nevertheless, we have clinically demonstrated that regions with perfusion defects on MCE performed several days postinfarction and after hyperemia has abated do not demonstrate recovery in function even after revascularization.15 18
The scatter between MCE perfusion size and radiolabeled microsphere-derived blood flow (Fig 9) is to be expected. Microspheres do not have the resolution of MCE; therefore, the precise transmural location of infarction cannot be ascertained by use of this technique, which divides myocardial thickness into three pieces compared with MCE, which has a spatial resolution of 0.8 mm. The major point of Fig 9 is to show that total perfusion to the infarct bed is less with larger infarcts, which tend to be more transmural, and greater with smaller infarcts, which tend to be located within the endocardium, and that these perfusion defects do indeed reflect flow abnormalities.
Although we placed stenoses of various severity in the dogs, which produced attenuation of the hyperemic response that ranged from mild to extreme, the study design precluded detailed analysis of the effect of different severities of coronary stenoses on perfusion defect size and contractile reserve in the same dog. Such data could be useful for a more complete understanding of the relationship between blood flow and contractile reserve and the effects of these interactions on MCE perfusion defect size.
Clinical Implications of the Study
Methods used clinically to determine infarct size in vivo have been limited by their poor spatial resolution.43 44 45 As a consequence, viability after infarction has been determined by indirect means such as myocardial metabolic activity and contractile reserve. The former is the basis for single-photon46 and positron emission47 imaging, and the latter forms the basis for dobutamine echocardiography.10 11 12 13 The ideal imaging method to assess viability should be able to delineate infarcted and noninfarcted tissue with adequate spatial resolution. Our results indicate that MCE has the ability to do this through its definition of the spatial distribution of abnormal microvascular reserve. On the basis of these results, regions with markedly abnormal microvascular reserve are nonviable, whereas those with normal microvascular reserve are normal. These principles have been confirmed more recently by positron emission tomography.48
The results of the present study should serve as the pathophysiological basis for clinical studies that use dobutamine echocardiography and MCE for the assessment of myocardial viability after infarction. The results, however, pertain only to the immediate postreperfusion period. Whether they can be extrapolated to hours or days after reperfusion is not known. Second-generation contrast agents49 50 and newer echocardiographic approaches to detect these agents within the myocardium, such as intermittent harmonic imaging,51 will aid in procurement of similar results in patients with the use of venous injection of contrast. The limitations inherent to echocardiography, including the lack of high-quality images in many patients when the transthoracic approach is used, will have to be addressed in clinical studies. Furthermore, whether semiquantitative or qualitative assessment of regional function and perfusion, which is routinely used in clinical echocardiography, will provide similar results also needs to be addressed in clinical studies. Such studies should be forthcoming in the near future.
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Acknowledgments |
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This study was supported in part by grants from the National Institutes of Health (R01-HL-48890), Bethesda, Md (Dr Kaul); the Virginia Affiliate of the American Heart Association, Glen Allen, Va (Dr Sklenar); and Molecular Biosystems, Inc, San Diego, Calif, and an equipment grant from General Electric Medical Systems, Milwaukee, Wis. Drs Ismail and Camarano were the recipients of fellowship training grants from the Virginia Affiliate of the American Heart Association and Mallinckrodt Medical Inc, St Louis, Mo, respectively. Dr Kaul is an Established Investigator of the National Center of the American Heart Association, Dallas, Tex.
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Footnotes |
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Presented in part at the 44th Annual Scientific Session of the American College of Cardiology, New Orleans, La, March 1995, and at the 45th Annual Scientific Session of the American College of Cardiology, Orlando, Fla, March 1996.
Received February 8, 1996; revision received March 21, 1996; accepted March 26, 1996.
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Braunwald E, Kloner RA. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation. 1982;66:1146-1149.
2.
Ross J Jr. Assessment of ischemic regional myocardial dysfunction and its reversibility. Circulation. 1986;74:1186-1190.
3. Touchstone DA, Beller GA, Nygaard TW, Tedesco C, Kaul S. Effects of successful intravenous reperfusion therapy on regional myocardial function and geometry in man: a tomographic assessment using two-dimensional echocardiography. J Am Coll Cardiol. 1989;13:1506-1513.[Abstract]
4. Charuzi Y, Beeder C, Marshall LA, Sasaki H, Pack NB, Geft I, Ganz W. Improvement in regional and global left ventricular function after intracoronary thrombolysis: assessment with two-dimensional echocardiography. Am J Cardiol. 1984;53:662-665.[Medline] [Order article via Infotrieve]
5.
Widimsky P, Cervenka V, Visek V, Sladkova T, Dvorak J, Hrdlicka S. First month course of left ventricular asynergy after intracoronary thrombolysis in acute myocardial infarction: a longitudinal echocardiographic study. Eur Heart J. 1985;6:759-765.
6. Penco M, Romano S, Agati L, Dagianti A, Vitarelli A, Fedele F, Dagianti A. Influence of reperfusion induced by thrombolytic treatment on natural history of left ventricular regional motion abnormality in acute myocardial infarction. Am J Cardiol. 1993;71:1015-1020.[Medline] [Order article via Infotrieve]
7.
Myers JH, Stirling MC, Choy M, Buda AJ, Gallagher KP. Direct measurement of inner and outer wall thickening dynamics with epicardial echocardiography. Circulation. 1986;74:164-172.
8.
Weintraub WS, Hattori S, Aggarwal JB, Bodenheimer MM, Banka V, Helfant RH. The relationship between myocardial blood flow and contraction by myocardial layer in the canine left ventricle during ischemia. Circ Res. 1981;48:430-438.
9.
Vatner SF. Correlation between acute reductions in myocardial blood flow and function in conscious dogs. Circ Res. 1980;47:201-207.
10. Pierard L, De Landsheere CM, Berthe C, Rigo P, Kulbertus HE. Identification of viable myocardium by echocardiography during dobutamine infusion in patients with myocardial infarction after thrombolytic therapy: comparison with positron emission tomography. J Am Coll Cardiol. 1990;15:1021-1031.[Abstract]
11. Barilla F, Gheorghiade M, Alam M, Khaja F, Goldstein S. Low-dose dobutamine in patients with acute myocardial infarction identifies viable but not contractile myocardium and predicts the magnitude of improvement in wall motion abnormalities in response to coronary revascularization. Am Heart J. 1991;122:1522-1531.[Medline] [Order article via Infotrieve]
12.
Smart SC, Sawada SC, Ryan T, Atherton L, Segar DS, Atherton L, Berkovitz K, Bourdillon PDV, Feigenbaum H. Low-dose dobutamine echocardiography detects reversible dysfunction after thrombolytic therapy of acute myocardial infarction. Circulation. 1993;88:405-415.
13. Baer FM, Voth E, Deutsch HJ, Schneider CA, Schicha H, Sechtem U. Assessment of viable myocardium by dobutamine transesophageal echocardiography and comparison with fluorine-18 fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol. 1994;24:343-353.[Abstract]
14.
Ito H, Tomooka T, Sakai N, Yu H, Higashino Y, Fujii K, Masuyama T, Kitabatake A, Minamino T. Lack of myocardial perfusion immediately after successful thrombolysis: a predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation. 1992;85:1699-1705.
15.
Ragosta M, Camarano GP, Kaul S, Powers E, Gimple LW. Microvascular integrity indicates myocellular viability in patients with recent myocardial infarction: new insights using myocardial contrast echocardiography. Circulation. 1994;89:2562-2569.
16. Lim Y-J, Nanto S, Masuyama T, Kohama A, Hori M, Kamada T. Myocardial salvage: its assessment and prediction by the analysis of serial myocardial contrast echocardiograms in patients with acute myocardial infarction. Am Heart J. 1994;128:649-656.[Medline] [Order article via Infotrieve]
17. Agati L, Voci P, Bilotta F, Luongo R, Autore C, Penco M, Iacobini C, Fedele F, Dagianti A. Influence of residual perfusion within the infarct zone on the natural history of left ventricular dysfunction after acute myocardial infarction: a myocardial contrast echocardiographic study. J Am Coll Cardiol. 1994;24:336-342.[Abstract]
18. Camarano G, Ragosta M, Gimple LW, Powers ER, Kaul S. Identification of viable myocardium with contrast echocardiography in patients with poor left ventricular systolic function caused by recent or remote myocardial infarction. Am J Cardiol. 1995;75:215-219.[Medline] [Order article via Infotrieve]
19.
Stahl LD, Aversano TR, Becker LC. Selective enhancement of function of stunned myocardium by increased flow. Circulation. 1986;74:843-851.
20. Becker LC, Levine JH, DiPaula AF, Guarnieri T, Aversano T. Reversal of dysfunction in postischemic stunned myocardium by epinephrine and postextrasystolic potentiation. J Am Coll Cardiol. 1986;7:580-589.[Abstract]
21. Sklenar J, Villanueva FS, Glasheen WP, Ismail S, Goodman NC, Kaul S. Dobutamine echocardiography for determining the extent of myocardial salvage after reperfusion: an experimental evaluation. Circulation. 1994;90:1503-1512.
22. Bolli R, Zhu W, Myers ML, Hartley CJ, Roberts R. Beta-adrenergic stimulation reverses postischemic myocardial dysfunction without producing subsequent functional deterioration. Am J Cardiol. 1985;56:964-968.[Medline] [Order article via Infotrieve]
23. Kloner RA, Ganote CE, Jennings RB. The `no-reflow' phenomenon after temporary coronary occlusion in the dog. J Clin Invest. 1974;54:1496-1508.
24.
Villanueva FS, Glasheen WP, Sklenar J, Kaul S. Characterization of spatial patterns of flow within the reperfused myocardium by myocardial contrast echocardiography: implications for determining extent of myocardial salvage. Circulation. 1993;88:2596-2606.
25. White FC, Sanders M, Bloor CM. Regional redistribution of myocardial blood flow after coronary occlusion and reperfusion in the conscious dog. Am J Cardiol. 1978;42:234-243.[Medline] [Order article via Infotrieve]
26. Cobb FR, Bache RJ, Rivas F, Greenfield JC. Local effects of acute cellular injury on regional myocardial blood flow. J Clin Invest. 1976;57:1359-1368.
27. McGillem MJ, DeBoer SF, Friedman HZ, Mancini GBJ. The effects of dobutamine on regional function in the presence of rigid coronary stenoses and subcritical impairments of reactive hyperemia. Am Heart J. 1988;115:970-977.[Medline] [Order article via Infotrieve]
28. Keller MW, Glasheen WP, Kaul S. Albunex®: a safe and effective commercially produced agent for myocardial contrast echocardiography. J Am Soc Echocardiogr. 1989;2:48-52.[Medline] [Order article via Infotrieve]
29.
Ten Cate FJ, Widimsky P, Cornel JH, Waldstein DJ, Serruys PW, Waaler A. Intracoronary Albunex: its effect on left ventricular hemodynamics, function, and coronary sinus flow in humans. Circulation. 1993;88:2123-2127.
30. Jayaweera AR, Matthew TL, Sklenar J, Spotnitz WD, Watson DD, Kaul S. Method for the quantitation of myocardial perfusion during myocardial contrast two-dimensional echocardiography. J Am Soc Echocardiogr. 1990;3:91-98.[Medline] [Order article via Infotrieve]
31.
Villanueva FS, Glasheen WP, Sklenar J, Jayaweera AR, Kaul S. Successful and reproducible myocardial opacification during two-dimensional echocardiography from right heart injection of contrast. Circulation. 1992;85:1557-1564.
32. Sklenar J, Jayaweera AR, Kaul S. A computer-aided approach for the quantitation of left ventricular function using two-dimensional echocardiography. J Am Soc Echocardiogr. 1992;5:33-40.[Medline] [Order article via Infotrieve]
33. Press WH, Flannery BP, Teukolsky SA, Vetterling WT. Numerical Recipes in C: The Art of Scientific Computing. Cambridge, Mass: Cambridge University Press; 1988.
34. Fishbein MC, Meerbaum S, Rit J, Lando U, Kanmatsuse K, Mercier JC, Corday E, Ganz W. Early phase acute myocardial infarct size quantification: validation of the triphenyl tetrazolium chloride tissue enzyme staining technique. Am Heart J. 1981;101:593-600.[Medline] [Order article via Infotrieve]
35. Heymann MA, Payne BD, Hoffman JI, Rudolph AM. Blood flow measurements with radionuclide-labeled particles. Prog Cardiovasc Dis. 1977;20:55-79.[Medline] [Order article via Infotrieve]
36. Kaul S, Kelly P, Oliner JD, Glasheen WP, Keller MW, Watson DD. Assessment of regional myocardial blood flow in-vivo with myocardial contrast two-dimensional echocardiography. J Am Coll Cardiol. 1989;13:468-482.[Abstract]
37.
Kemper AJ, O'Boyle JE, Cohen CA, Taylor A, Parisi AF. Hydrogen peroxide contrast echocardiography: quantification in vivo of myocardial risk area during coronary occlusion and of the necrotic area remaining after myocardial reperfusion. Circulation. 1984;70:309-317.
38.
Ismail S, Jayaweera AR, Goodman NC, Camarano GP, Skyba DM, Kaul S. Detection of coronary artery stenoses and quantification of blood flow mismatch during coronary hyperemia with myocardial contrast echocardiography. Circulation. 1995;91:821-830.
39. Bolli R, Triana F, Jeroudi MO. Prolonged impairment of coro nary vasodilation after reversible ischemia. Circ Res. 1990;67:67:332-343.
40.
Weyman AE, Franklin TD, Hogan RD, Gillam LD, Wiske PS, Newell JB, Gibbons EF, Foale RA. Importance of temporal heterogeneity in assessing the contraction abnormalities associated with acute myocardial ischemia. Circulation. 1984;70:102-112.
41.
Gillam LD, Hogan RD, Foale RA, Franklin TD, Newell JB, Guyer DE, Weyman AE. A comparison of quantitative echocardiographic methods for delineating infarct-induced abnormal wall motion. Circulation. 1984;70:113-122.
42.
Zeiher AM, Wollschalger H, Bonzel T, Kasper W, Just H. Hierarchy of levels of ischemia-induced impairment in regional left ventricular systolic function in man. Circulation. 1987;76:768-776.
43.
Buja LM, Parkey RW, Dees JH, Stokely EM, Harris RA Jr, Bonte FJ, Willerson JT. Morphologic correlates of technetium-99m stannous pyrophosphate imaging of acute myocardial infarcts in dogs. Circulation. 1975;52:596-607.
44.
Khaw BA, Yasuda T, Gold HK, Leinbach RC, Johns JA, Kanke M, Barlai-Kovach M, Strauss HW, Haber E. Acute myocardial infarct imaging with indium-111-labeled monoclonal antimyosin Fab. J Nucl Med. 1987;28:1671-1678.
45.
Johnson LL, Seldin DW, Keller AM, Wall RM, Bhatia K, Bingham CO, Tresgallo ME. Dual isotope thallium and indium antimyosin SPECT imaging to identify acute infarct patients at further ischemic risk. Circulation. 1990;81:37-45.
46.
Sabia PJ, Powers ER, Ragosta M, Watson DD, Smith WH, Kaul S. Role of quantitative planar thallium-201 imaging for predicting viability in patients with acute myocardial infarction and a totally occluded infarct-related artery. J Nucl Med. 1993;34:728-736.
47. Schelbert HR. Metabolic imaging to assess myocardial viability. J Nucl Med. 1994;35(suppl):8S-14S.
48.
Maes A, Van de Werf F, Nuyts J, Bormans G, Desmet W, Mortelmans L. Impaired myocardial tissue perfusion early after successful thrombolysis: impact on myocardial flow, metabolism, and function on late follow-up. Circulation. 1995;92:2072-2078.
49. Camarano GP, Ismail S, Goodman NC, Kaul S. Assessment of risk area during coronary occlusion and infarct size after reperfusion can be determined with myocardial contrast echocardiography using intravenous injections of FS-069, a new contrast agent. Circulation. 1994;90(suppl I):I-68. Abstract.
50. Arai A, Kenny A, Shiota T, Unger E, Yellowhair D, Passafini A, Matsunaga T, Grauer SE, Pantley G, Sahn DJ. Transpulmonary passage of Aerosomes(TM), a pressure stable, lipid-based echocardiographic contrast agent: studies in pigs. J Am Coll Cardiol. 1994;23:25A. Abstract.
51.
Porter TR, Xie F. Transient myocardial contrast after initial exposure to diagnostic ultrasound pressures with minute doses of intravenously injected microbubbles: demonstration of potential mechanisms. Circulation. 1995;92:2391-2395.
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