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(Circulation. 1996;94:748-754.)
© 1996 American Heart Association, Inc.
Articles |
Coronary Reserve Abnormalities in the Infarcted Myocardium
Assessment of Myocardial Viability Immediately Versus Late After Reflow by Contrast Echocardiography
the Cardiovascular Division, University of Virginia School of Medicine, Charlottesville.
Correspondence to Sanjiv Kaul, MD, Cardiovascular Division, Box 158, University of Virginia Medical Center, Charlottesville, VA 22908.
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Abstract |
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Background The aim of this study was to determine whether myocardial contrast echocardiography (MCE) during exogenous vasodilation can accurately delineate infarct size, and hence the extent of myocardial viability, both immediately (15 minutes) and late (3 hours) after reperfusion when postreflow coronary hyperemia is still present.
Methods and Results Twenty-one open-chest anesthetized dogs underwent 3 to 6 hours of coronary occlusion followed by reperfusion. MCE was performed 15 minutes after reflow before and during infusion of 0.2 mg·kg-1·min-1 adenosine IV. In 12 dogs, infarct size was measured at this time. In the remaining 9 dogs, reperfusion was continued for 3 hours, when MCE was repeated before and after an infusion of 0.56 mg·kg-1·min-1 dipyridamole IV and infarct size was measured. In the absence of adenosine, MCE perfusion defect at 15 minutes underestimated infarct sizes at both 15 minutes and 3 hours, whereas in the presence of adenosine, the estimate of infarct size was more accurate. Similarly, in the absence of dipyridamole, although MCE perfusion defect underestimated infarct size (both measured 3 hours after reflow), in the presence of dipyridamole, the estimate of infarct size was more accurate.
Conclusions By unmasking abnormalities in flow reserve within the infarct bed, MCE in conjunction with coronary vasodilators can accurately predict infarct size both 15 minutes and 3 hours after reperfusion. Thus, MCE can be used for assessing the extent of myocardial viability both immediately and late after reperfusion when postreflow coronary hyperemia is still present.
Key Words: myocardium • echocardiography • vasodilation • infarction
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Introduction |
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When patency of an occluded coronary artery is restored in the setting of acute myocardial infarction, the nature of subsequent perfusion to the postischemic bed is complex and variable. Blood flow to the reperfused infarct bed immediately after reflow is characterized by a combination of hyperemia, low-reflow, and no-reflow.1 2 3 4 5 6 7 Even when perfusion remains relatively preserved in regions with myocyte death, abnormalities in microvascular reserve are seen in these areas.8 9
Because of these pathophysiological properties of postischemic tissue, a flow-tracer technique, such as MCE, can uniquely delineate the temporal and spatial variability of blood flow to reperfused myocardium.9 Using a combination of no-reflow and impaired coronary reserve, which typifies infarcted tissue, we have previously demonstrated that in the presence of exogenous vasodilation, MCE can discriminate between viable and necrotic myocardium and thus can be used to assess the extent of myocardial salvage when performed 3 hours after reperfusion.10
In the clinical setting, immediate therapeutic decisions after reperfusion therapy may require relatively instantaneous (within minutes) rather than delayed (several hours) knowledge of the extent of viable versus necrotic myocardium. The aim of this investigation, therefore, was to assess whether MCE during exogenous vasodilation can accurately delineate infarct size and hence the extent of myocardial viability both immediately (15 minutes) and late (3 hours) after reperfusion when postreflow hyperemia is still present. An open-chest canine model of coronary occlusion and reperfusion was used for the study.
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Methods |
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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. Twenty-one mongrel dogs were used for the experiment. They were anesthetized with 30 mg/kg sodium pentobarbital (Abbott Laboratories), intubated, and mechanically ventilated with a respirator pump (model 607, Harvard Apparatus). A 7F polyethylene catheter was placed in each femoral artery for reference sample withdrawal during radiolabeled microsphere injection. One of these catheters was also used for arterial pressure monitoring. A femoral vein was also cannulated with a 7F catheter for intravenous infusion of fluids 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 catheter was placed in the left atrium for injection of radiolabeled microspheres and for monitoring of left atrial pressure. The arterial and left atrial pressure catheters were attached to fluid-filled transducers, which were connected to a multichannel physiological recorder (model ES-2000, Gould Electronics). The proximal or middle portion of the LAD in 13 dogs or LCx in 8 dogs was dissected free from surrounding tissue and encircled by a snare to permit coronary occlusion.
Either of two catheter systems was used for injection of microbubbles. In 12 dogs, a 7F pigtail catheter was inserted into the left carotid artery via an 8F introducer sheath, and its tip was positioned in the proximal aortic root. In the remaining 9 dogs, the tip of a 3.5-cm-long 21-gauge polyethylene catheter was positioned in the aorta via retrograde cannulation of the LAD. Each catheter was connected to a power injector (model 3000, Liebel-Flarsheim Co) for administration of microbubbles.
Myocardial Contrast Echocardiography
MCE was performed with 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 kept constant throughout. A maximum dynamic range of 72 dB was used. A saline bath was used as an acoustic interface between the heart and the transducer. Imaging was performed in the short-axis plane at the mid–papillary muscle level, with the same level carefully identified at each stage to permit serial image comparisons within each experiment. MCE data were recorded on 1.25-cm VHS videotape with a high-fidelity recorder (Panasonic model AG6200, Matsushita Electrical Co).
Sonicated albumin microbubbles with a mean size of 4.3 µm and concentration of 0.5 billion/mL (Albunex, Molecular Biosystems Inc) were used as the contrast agent. In the doses used in this study, it has been shown that this product does not significantly alter systemic or coronary hemodynamics.11 12 These microbubbles were power-injected into the aorta during simultaneously performed echocardiographic imaging. To achieve adequate myocardial opacification, 5 to 10 mL of contrast was required for the pigtail catheter and 1 to 3 mL was necessary for the angiocatheter. Although the dose of microbubbles required for optimal myocardial opacification varied between dogs, the same dose was used in each dog.
Our approach to the off-line analysis of echo images has been described previously.10 13 Videotaped MCE images were digitized to the image memory of a computer (Mipron, Kontron) in a 244x244x8-bit format. A single contrast-enhanced end-diastolic frame depicting the maximum disparity in contrast effect between the LAD and LCx beds was aligned with an end-diastolic precontrast frame by use of computer cross-correlation.14 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. To optimally portray defect borders, each pixel was assigned a color based on the degree of contrast enhancement, whereby shades of red, progressing to hues of orange, yellow, and white, represented incremental contrast opacification. Areas demonstrating no increase in video intensity were not assigned a color. With this technique, regions without contrast enhancement during coronary occlusion represent risk area, whereas areas with relative contrast deficiency during reperfusion correspond to zones of relative hypoperfusion within the infarct bed.15 16 17 18 Contrast defects were planimetered and expressed as a percentage of the left ventricular myocardium in the short-axis slice.
Infarct Size Determination
At the conclusion of the experiment, the heart was excised and sectioned into 1-cm-thick short-axis slices parallel to the AV groove. The slice corresponding to the MCE 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°C for 20 minutes, followed by fixation in 10% formalin. This technique stains viable myocardium brick red and spares necrotic areas, which appear unstained.19 An image of the short-axis slice was digitized into the off-line computer with a video camera (66 series, Date-MTI Corp). Infarct size was determined by planimetry of the unstained portions of the digitized image and was expressed as a percentage of the left ventricular short-axis area.
Measurement of Myocardial Blood Flow
Regional myocardial blood flow was measured by use of radiolabeled microspheres.20 For each stage, 
2 million 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 with a timed withdrawal pump (model 944, Harvard Apparatus). Postmortem, the left ventricular short-axis slice corresponding 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 with a custom-designed computer program.21 Flow to each sample was calculated according to 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 (mL/min), 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 (lateral borders with intermediate levels of flow thus excluded) was normalized to flow in the nonischemic bed.
Experimental Protocol
After baseline MCE, the LAD or LCx was occluded for 3 to 6 hours to produce infarcts of various degrees of transmurality.22 At the end of the occlusion period, MCE was performed to determine the risk area. After the occlusion was released, MCE was repeated in all 21 dogs 15 minutes after reflow, and radiolabeled microsphere flows were measured in 17 dogs both before and during an infusion of adenosine (0.2 mg·kg-1·min-1 IV). Twelve of the dogs were then killed, and in the remaining 9 dogs, reperfusion was continued for a total of 3 hours, after which MCE and blood flow measurements were repeated before and 5 minutes after the infusion of dipyridamole (0.56 mg/kg IV). Our previous data indicate that MCE at 3 hours of reflow in the presence of dipyridamole can accurately delineate infarct size.10 Adenosine was chosen for the 15-minute stage because its short duration of action would minimize any potential effects of the drug itself on infarct size or reperfusion injury during the subsequent 3 hours.23 The duration of adenosine infusion was <10 minutes.
Statistical Methods
Data were expressed as mean±SD. Within-group comparisons were made by paired Student's t test. Correlations between MCE- and TTC- or microsphere-derived variables were made by linear regression analysis. Statistical significance was defined as P<.05 (two-sided).
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Results |
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Relationship Between MCE Defect Size After 15 Minutes of Reflow and Infarct Size
When performed 15 minutes after reperfusion, MCE predicted infarct size most accurately in the presence of adenosine. Fig 1
depicts data from a dog that underwent LCx occlusion. After 15 minutes of reflow, there is posterolateral wall perfusion defect (Fig 1A) corresponding to the region of true no-reflow, in which microsphere-derived blood flow was one eighth of the flow to the LAD bed. The perfusion defect, however, underestimates the infarct size measured with TTC 15 minutes after reflow (Fig 1C). With the addition of adenosine, the perfusion defect appears larger and more dense (Fig 1B) and more closely approximates the infarction.
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Figs 2 and 3 summarize the relationship between infarct size and MCE defect size at 15 minutes of reflow before and during adenosine infusion, respectively, in all dogs, including the 9 that underwent 3 hours of reperfusion and in which infarct size was measured 3 hours rather than 15 minutes after reperfusion. In the absence of adenosine (Fig 2), MCE systematically underestimated infarct size measured after either 15 minutes or 3 hours of reperfusion. In comparison, MCE during adenosine infusion at 15 minutes of reflow (Fig 3) resulted in larger perfusion defects that closely predicted infarct size, with a linear relationship approaching the line of identity. Importantly, adenosine MCE performed 15 minutes after reflow accurately predicted TTC-determined infarct size measured both 15 minutes and 3 hours after reperfusion (Fig 3).
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) or 3 hours (
) after reperfusion. See text for details.
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Relationship Between MCE Defect Size After 3 Hours of Reflow and Infarct Size
MCE performed after 3 hours of reflow was predictive of the extent of infarction only in the presence of pharmacological vasodilation, as illustrated in Fig 4, which depicts 3 hours of MCE data in a dog with anterior infarction. MCE without dipyridamole demonstrated scarcely any perfusion abnormality. In comparison, 3 hours of MCE data after dipyridamole revealed a defect (Fig 4B) that closely corresponded to infarct size (Fig 4C), showing contrast only in the nonischemic LCx bed and viable anterior epicardium. The relationship between 3-hour MCE defect and infarct size in the presence of dipyridamole is summarized in Fig 5, which shows a linear relationship between perfusion defect size and the extent of infarction. No such relationship was found at 3 hours in the absence of dipyridamole (r=-.10).
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Comparison Between 15-Minute and 3-Hour MCE Perfusion Patterns
In the 9 dogs with MCE data both early and late after reperfusion, MCE defects without vasodilation tended to be larger at 15 minutes (13.2±8.7%) than at 3 hours (6.3±5.8%) of reflow (see also Figs 1 and 4
), although this difference was not statistically significant (P=.11). There was no significant difference between perfusion defect size during pharmacological vasodilation at 15 minutes (24.3±5.6%) and 3 hours (22.6±3.5%) of reperfusion (P=.17).
Relationship Between MCE Findings and Regional Myocardial Blood Flow
Radiolabeled microsphere-derived blood flow was measured in 17 of the 21 dogs. The relationship between perfusion defect size and endocardial flow after reperfusion at all stages is illustrated in Fig 6. There was an inverse relationship between the size of the MCE defects and normalized endocardial flow to the risk area, confirming that larger MCE defects corresponded to more extensive hypoperfusion and smaller defects represented relatively preserved flow to the risk area. In the 9 dogs with MCE data obtained at both times after reflow, the normalized endocardial flows in the absence of coronary vasodilators were lower 15 minutes (0.77±0.71) than 3 hours (1.27±0.72) after reperfusion (P=.01).
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Although transmural blood flow to the risk area after 15 minutes of reperfusion was slightly greater than that to the nonischemic bed (normalized flow, 1.19±0.54), there was a significant decrease in normalized flow after administration of adenosine at the 15-minute reflow stage (0.46±0.33, P<.001). Similarly, flow to the risk bed at 3 hours was comparable to that in the normal bed (normalized flow, 1.01±0.43) but decreased relative to that in the nonischemic bed after dipyridamole (normalized flow, 0.41±0.14, P<.002). These data confirm that the larger MCE defects seen during adenosine or dipyridamole infusion compared with those without vasodilation were a result of a lesser increase in hyperemic flow to the infarct compared with the normal bed.
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Discussion |
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The new finding in the present study is that although there is fluctuation in basal flows within the infarct zone 15 minutes and 3 hours after reperfusion, abnormalities in coronary reserve at these times are similar, as evidenced by both MCE and radiolabeled-microsphere data. Therefore, MCE performed 15 minutes after reflow in conjunction with a coronary vasodilator accurately predicts the extent of infarction at the time of reflow as well as that measured 3 hours later.
Relationship Between Myocardial Blood Flow During Reperfusion and Infarct Size: MCE Without Pharmacological Vasodilation
This study confirms our previous observation that the spatial distribution of MCE perfusion defects during reflow in the absence of a coronary vasodilator varies with time and by itself underestimates the degree of necrosis.10 The radiolabeled microsphere data show that despite infarction, flow to the risk area up to several hours after reperfusion remains hyperemic or comparable to that in the nonischemic bed, accounting for the appearance of microbubbles even within regions of necrosis. This finding is consistent with that of Cobb et al,4 who found that early after reperfusion, blood flow to acutely injured areas remained higher than or equal to that in nonischemic regions. Similarly, White and coworkers2 found that the level of flow to infarcted regions immediately after reperfusion was poorly predictive of tissue viability.
In the present study, as in our previous one,10 the persistence of flow to the outer reaches of the infarct bed24 resulted in underestimation of the transmural extent of infarction when MCE was performed without a vasodilator. Nonetheless, subendocardial perfusion defects were often observed even without the use of vasodilators when the infarction was at least moderate in size (the example in Fig 4A is an exception). The inverse correlation between endocardial flow and MCE defect size even in the absence of a coronary vasodilator confirms that subendocardial defects on MCE corresponded to zones of true no-reflow, or low-reflow, which have been found histologically to represent regions of microvascular disruption or plugging within infarcted tissue.1 12 25 26 Generally, it has been observed that the spatial extent of the no-reflow phenomenon is less than but proportional to the spatial extent of necrosis.5 24 Our data support this observation, since we did find an approximate relationship between MCE defect and infarct size after 15 minutes of reperfusion even in the absence of a coronary vasodilator (Fig 2) when, as expected, the MCE defect size underestimated infarct size.
It is also of interest that MCE defects tended to be larger at 15 minutes than at 3 hours of reperfusion, which corresponded to lower subendocardial flow to the infarct bed at 15 minutes compared with 3 hours of reflow. We observed similar findings in our previous study,10 the reasons for which remain unclear. One possibility is that early after reperfusion, the infarct vessel may have spasm or residual thrombus and hence lack full patency, which resolves by 3 hours of reflow or after administration of a vasodilator.
Stability of the Abnormalities in Coronary Flow Reserve During Reperfusion: MCE During Pharmacological Vasodilation
Although MCE in the absence of pharmacological vasodilation consistently underestimated infarct size, the addition of adenosine or dipyridamole 15 minutes and 3 hours after reperfusion, respectively, resulted in perfusion defects that were highly predictive of infarct size. Even when hyperemic flow was present within the risk area after reflow, microvascular reserve was impaired such that flow to the risk area relative to that in the nonischemic bed was reduced during vasodilator stress. Although radiolabeled microspheres cannot resolve the exact spatial distribution of this abnormal reserve, MCE demonstrates that it occurred precisely within the region of necrosis.
Our data suggest not only that abnormal flow reserve after reperfusion is limited to infarcted tissue but also that it remains relatively stable 15 minutes and 3 hours after reperfusion. There are relatively few studies on the natural history of coronary reserve abnormalities during postinfarct reperfusion. VanHaecke et al9 showed that endogenous coronary reserve in viable postischemic tissue, as assessed by peak reactive hyperemia, is normal immediately after reperfusion, declines over a period of hours, but can be restored with adenosine. Johnson and colleagues8 demonstrated that the reduction in vascular conductance during maximal vasodilation in a postischemic bed remained unchanged over the course of 45 minutes of reperfusion. Our data extend these observations and imply that both the magnitude and the spatial extent of coronary reserve impairment remain relatively unchanged between 15 minutes and 3 hours of reperfusion.
In contradistinction to these studies, Bolli et al27 found that after LAD occlusion insufficient to cause necrosis in dogs, the hyperemic response to adenosine after reperfusion was less in the postischemic than in the nonischemic bed. Such data would suggest that maximal vasodilatory reserve is impaired even in nonnecrotic postischemic tissue and imply that MCE during pharmacological vasodilation could overestimate the extent of infarction by revealing contrast defects even in viable tissue. Bolli and colleagues occluded the vessel for a very brief period compared with our study (15 minutes instead of 3 to 6 hours) and measured blood flow later during reperfusion (at 4 hours of reperfusion rather than at 15 minutes and 3 hours as we did). It is therefore not possible to directly compare our results with those of these authors.
An important point in our study is that when MCE was performed during adenosine infusion 15 minutes after reflow, perfusion defect size correlated closely with TTC-determined infarct size measured either 15 minutes or 3 hours after reflow. That is, the spatial distribution of abnormal reserve at 15 minutes corresponded to infarct size determined at 3 hours. Furthermore, as demonstrated in the dogs that underwent only 15 minutes of reflow, the MCE defect during vasodilation at 15 minutes also corresponded to postmortem infarct size at 15 minutes. Hence, not only does the spatial distribution of abnormal reserve remain constant at 15 minutes and 3 hours of reperfusion, but this distribution at these two moments of reflow also corresponds to infarct size at those same moments. The correspondence between MCE defect size during exogenous vasodilation at 15 minutes and infarct size at 3 hours indirectly suggests that infarct size itself appears not to change during the reflow period, as other studies of reperfusion injury have previously debated.28 29 30 31
The relationship between infarct and MCE defect sizes during pharmacological vasodilation was somewhat closer at 15 minutes than at 3 hours, when underestimation of infarct size appeared to be smaller. There are several possible explanations for this apparent superiority of the 15-minute MCE data. It is likely that the presence of more points for the 15-minute compared with the 3-hour data gave a statistical advantage to the 15-minute measurement. Indeed, when the 9 dogs with MCE images during exogenous vasodilation at both time points were analyzed separately, there was no significant difference in contrast defect size at 15 minutes versus 3 hours. Another possibility is that maximal coronary reserve actually improved in the infarcted tissue during 3 hours of reperfusion, resulting in a worse correlation between MCE defect and infarct size at 3 hours. This is an unlikely scenario, since the microsphere data do not indicate a significant difference in flow disparity between the infarct and nonischemic beds during pharmacological vasodilation at the two times. It would thus be improbable that coronary flow reserve in infarcted tissue actually recovered at 3 hours.
Critique of Our Methods
Adenosine was chosen to elicit maximal vasodilation at 15 minutes, whereas dipyridamole was used for the 3-hour stage. Dipyridamole was used because of our previous experience with this agent during MCE performed 3 hours after reperfusion.10 Adenosine was administered for the 15-minute stage because its short half-life32 enabled reperfusion to continue for 3 hours without any prolonged drug effects confounding the results at 3 hours.23
Our image processing algorithm used color coding to optimize delineation of perfusion bed borders. This algorithm relies on peak video intensity as a marker of differences in blood flow and hence assumes a systematic relationship between microvascular bubble concentration and tissue perfusion. This is a reasonable assumption, for two reasons: First, we have shown that in the setting of pharmacological vasodilation, when changes in flow are modulated by changes in myocardial blood volume, alterations in peak intensity (which indicate the relative concentration of microbubbles in tissue) reflect alterations in blood flow.33 Second, by normalizing to peak video intensity in each image, the algorithm actually portrays relative flow, ie, differences in flow between the ischemic and nonischemic beds, which obviates the need to have a strictly linear relationship between flow and video intensity.
Only a subgroup of dogs underwent MCE imaging at both 15 minutes and 3 hours of reflow, thus lessening the number of dogs for whom comparisons between 15-minute and 3-hour data were possible. As stated earlier, this may have contributed to the apparently better statistical correlation between infarct size and MCE defects at 15 minutes (21 points) than at 3 hours (9 points). This experimental design was chosen because we thought it was important to document the relationship between MCE defect size during adenosine infusion at 15 minutes of reflow and infarct size present at that same time. Because reperfusion injury over the course of several hours could theoretically alter ultimate infarct size29 30 31 and hence render the 15-minute MCE defect poorly representative of "final" infarct size, we chose also to subject a subgroup of dogs to 3 hours of reperfusion to determine the relationship between 15-minute MCE patterns and "ultimate" infarct size measured several hours later.
Clinical Implications
In the immediate aftermath of acute infarction, myocardium within the reperfused bed contains a mixture of both necrotic and stunned but viable tissue.22 Differentiating infarcted from viable muscle in the acute postischemic setting is a difficult but crucial issue, since such distinctions significantly affect clinical decisions regarding the need for and expected benefit from therapeutic options such as revascularization, mechanical support, and/or medical management.34 35 36 The data from the present study suggest that MCE may enable such distinctions to be made not only late after reflow but also immediately after, thus allowing early formulation of treatment strategies based on the quantity of remaining viable myocardium.
With the emergence of new contrast imaging agents and echocardiographic technology,37 38 39 MCE has the potential for the rapid bedside assessment of tissue salvage after reperfusion. Clinical studies, however, will be limited by the lack of high-quality images in many patients. Furthermore, factors relating to chronic coronary disease not seen in acute animal models may also affect the results. These variables include the effect of chronic endothelial dysfunction on microbubble rheology,40 41 patchy rather than confluent necrosis precluding the exact delineation of infarct topography, and the lack of safety data of vasodilator drugs in the acute phase of myocardial infarction.42 To what extent these confounding variables will influence the clinical use of MCE can only be answered in future clinical studies.
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Acknowledgments |
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This study was supported 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 (Dr Sklenar); and Molecular Biosystems, Inc, San Diego, Calif, and an equipment grant from General Electric Medical Systems, Milwaukee, Wis. Drs Villanueva and Ismail were recipients of fellowship training grants from the Virginia Affiliate of the American Heart Association; Dr Camarano was the recipient of a fellowship training grant from Mallinckrodt Medical, Inc, St Louis, Mo; and Dr Kaul is an Established Investigator of the National Center of the American Heart Association, Dallas, Tex.
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Selected Abbreviations and Acronyms |
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Footnotes |
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Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November, 1993, and published in abstract form (Circulation. 1993;88[suppl I]:I-302).
Received November 29, 1995; revision received January 11, 1996; accepted February 20, 1996.
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