Myocardial Perfusion Patterns Related to Thrombolysis in Myocardial Infarction Perfusion Grades After Coronary Angioplasty in Patients With Acute Anterior Wall Myocardial Infarction
Background Epicardial coronary flow is occasionally reduced even after coronary intervention despite the absence of vessel obstruction in patients with acute myocardial infarction. Our aim was to clarify the cause and outcomes of radiocontrast slow filling in patients with reperfused acute anterior myocardial infarction by assessing microvascular damage with the use of myocardial contrast echocardiography (MCE) and functional outcomes.
Methods and Results We carefully reviewed the cineangiograms of 86 patients who achieved coronary revascularization within 12 hours of the onset and underwent MCE before and soon after recanalization with the intracoronary injection of sonicated microbubbles. Antegrade coronary flow after recanalization was graded by two observers based on Thrombolysis in Myocardial Infarction (TIMI) trial flow grades. Left ventricular ejection fraction was measured on the day of infarction and 1 month later. TIMI grade 2 was observed in 18 patients (21%), and the other 68 patients manifested TIMI grade 3 after recanalization. All patients with TIMI 2 showed substantial MCE no reflow, whereas only 11 patients (16%) with TIMI 3 showed MCE no reflow. Functional improvement was worse in patients with TIMI 2 than in those with TIMI 3 (TIMI 2, 38±8% versus 40±8%, P=NS [acute versus late]; TIMI 3, 44±13% versus 55±13%, P<.001). Among patients with TIMI 3, significant functional improvement was observed only in patients with MCE reflow (MCE reflow, 46±13% versus 57±12%, P<.001; MCE no reflow, 35±11% versus 45±12%, P=NS).
Conclusions Despite no obstructive lesion of the vessel, TIMI 2 is caused by advanced microvascular damage and is a highly specific, although not sensitive, predictor of poor functional outcomes in patients with acute myocardial infarction. TIMI 3 does not necessarily indicate myocardial salvage, and detection of MCE no reflow in these patients is particularly useful for the prediction of functional outcome.
Coronary reperfusion through the use of thrombolysis and/or coronary angioplasty is established as an essential therapy for acute myocardial infarction. Originally, its benefit was considered to be accomplished through timely reestablishment and maintenance of blood flow to the coronary artery previously occluded by thrombus. Several studies, however, documented that antegrade flow of the epicardial coronary artery is occasionally reduced profoundly during percutaneous coronary intervention.1 2 3 The reduction in coronary flow may be caused by damage to the epicardial vessels (dissection), focal spasm of the epicardial vessels, and embolization of the distal vessels by the plaque or thrombus, and in such circumstances additional interventions such as repeat angioplasty and coronary artery bypass graft are attempted to maintain vascular patency. However, coronary flow is occasionally markedly reduced even in patients with reperfused acute myocardial infarction and without any residual vessel obstruction. In such patients, the reduction in coronary flow may suggest the existence of microvascular dysfunction. However, there is little clinical evidence to support this hypothesis.
Severe ischemia causes microvascular damage in the areas of myocardial necrosis (no-reflow phenomenon).4 5 6 7 8 9 In recent clinical studies, myocardial contrast echocardiography (MCE) was used to show that ischemic episodes often break down the coronary microvasculature and that the patent epicardial coronary vessel per se does not necessarily guarantee perfusion at the microvascular level in patients with acute myocardial infarction. Thus, although there might be a discrepancy between angiographic findings of epicardial coronary artery flow and MCE findings of myocardial perfusion at the microvascular level, there are no systematic data regarding their relation.
To establish the relation, we reviewed the coronary cineangiograms of the patients with acute anterior wall myocardial infarction who underwent MCE before and after successful coronary angioplasty. The antegrade radiocontrast flow after the intervention was graded with the grading system of the Thrombolysis in Myocardial Infarction (TIMI) trial study group as it is most widely used. We assessed the incidence of TIMI grade 2 in patients without an apparent vessel obstruction, and its outcome was studied from the left ventricular functional viewpoint. In addition, we studied the relation between TIMI flow grading and microvascular dysfunction assessed with MCE.
This study was designed retrospectively. We carefully reviewed coronary angiographic recordings of 98 patients who met the following criteria: (1) hospitalized with the diagnosis of first acute anterior wall myocardial infarction, (2) one-vessel disease, (3) underwent coronary angioplasty to the totally or subtotally occluded infarct-related artery (TIMI grade 0 or 1) within 12 hours of the onset of the chest pain, (4) residual diameter stenosis of <50%, (5) underwent MCE before and after coronary recanalization, and (6) no cardiac death or no ischemic event during follow-up. The diagnosis of acute myocardial infarction was made on the basis of chest pain of ≥30 minutes’ duration occurring within 6 hours of presentation, ST-segment elevation of ≥2 mm in two contiguous ECG leads, and more than threefold increase in serum creatine kinase levels. Twelve patients were excluded from the analysis due to inadequate cineangiogram for evaluation of TIMI flow grade (five patients), incomplete coronary recanalization (residual diameter stenosis of ≥50%, flow-restricting dissection, or distal embolization) (four patients), and inadequate echocardiographic image quality (three patients). Therefore, this report is based on the remaining 86 patients (67 men and 19 women; mean age, 58 years; age range, 38 to 75 years). Seventy-one patients subsequently developed Q waves on 12-lead surface ECG, and the other 15 patients manifested non–Q wave myocardial infarction. Informed consent was obtained from each patient by one of the investigators. The study protocol was approved by the hospital’s Ethics Committee.
Catheterization was performed by using the femoral approach in the acute stage. Each patient rested in the supine position. All patients were pretreated with an injection of 100 U/kg heparin in the catheter laboratory. On completion of the diagnostic coronary angiography and left ventriculography, 2 mL of sonicated Ioxaglate (Hexabrix-360, Tanabe) containing sonicated microbubbles (a mean size of 12 μm) was injected into the left coronary artery for MCE. A commercially available mechanical sector scanner was used (model SAL-38B, Toshiba; carrier frequency of 3.5 MHz). Imaging of the apical long-axis view was initiated ≈10 seconds before the contrast injection and was continued for an average of 30 seconds with constant gain setting. MCE images were recorded on 1.25-cm videotape with a VHS recorder (model BR-6000, Victor). MCE was repeated with the contrast injection into the right coronary artery. Lead II ECG was continuously monitored during and after MCE. Intracoronary nitroglycerin (300 μg) and intravenous aspirin were given before coronary angioplasty. If required, intravenous heparin was added to prolong the activated clotting time (ACT) to >300 seconds. Angioplasty was performed with the use of an exchangeable guide wire system. An attempt was made to reduce the degree of residual stenosis at all regions within the infarct-related artery vessel <50% with restoration of flow. At a mean of 16 minutes after coronary recanalization, coronary angiography was repeated with a 6F diagnostic catheter, and the right anterior oblique projection was recorded for the evaluation of TIMI flow grade. MCE was repeated immediately after that with the use of the same procedure previously mentioned.
Two-dimensional echocardiography was performed before coronary intervention and at a mean of 24 days after the infarction with a commercially available electrical sector scanner (model SSH-65A, SSH-260A, Toshiba; carrier frequency of 3.75 or 2.5 MHz). In each echocardiographic examination, the parasternal long-axis view, the short-axis views at the levels of the mitral valve and midpapillary muscle, and the apical long-axis view were monitored and recorded on 1.25-cm videotape.
Coronary angiography and left ventriculography were repeated at a mean of 25 days after the infarction (24 to 29 days) with the right brachial approach. All medications were withdrawn at least 12 hours before cardiac catheterization.
Analysis of Echocardiographic Data
MCE images were analyzed by an experienced echocardiographer with the use of a commercially available image-analyzing system (Color Cardiology Workstation, TomTec or LA-500, PIAS). End-diastolic images of the apical long-axis view were digitized gating to the upstroke of the R wave, starting with two cycles before the onset of contrast enhancement visible in the myocardium. The image showing the brightest intensity was used for the following analysis. The areas at risk and of no reflow phenomenon were defined as contrast perfusion defects before and after coronary recanalization, respectively. The area of no reflow phenomenon was expressed as a ratio to the risk area. When the ratio exceeded 25%, myocardial reperfusion in the corresponding segment was considered to be incomplete (MCE no reflow). If this ratio was ≤25%, we considered myocardial reperfusion to be adequate (MCE reflow). In patients with MCE no reflow, the area of no reflow phenomenon was also expressed as the ratio to the risk area and to that of the left ventricular myocardium. Contrast defects are always clearly defined, and measurements of the size of the residual contrast defect are highly reproducible, as previously mentioned.10 11
Measurement of wall motion score (WMS) has been described previously.10 In brief, the left ventricle was divided into 17 segments (8 segments on each short-axis slice at the levels of the mitral valve and midpapillary muscle and the apical segment on the apical long-axis view), and each segment was scored with the following system: 3 indicates dyskinetic/akinetic; 2, severely hypokinetic; 1, hypokinetic; and 0, normal. Hyperkinesis is not given a score. The sum of each segmental score was defined as WMS. In the evaluation of the segmental wall motion abnormalities, we carefully examined the systolic thickening in the central portion of each segment. Segmental score was determined by two independent observers who were unaware of clinical data. In cases of disagreement, consensus was established by a third observer.
Analysis of Catheterization Data
After mechanical causes of flow reduction were excluded, such as critical residual coronary stenosis, apparent dissection, thrombosis, and/or distal vessel cutoff suggestive of macroembolization, the antegrade radiocontrast flow of the infarct-related artery was determined on the final coronary angiogram by two radiologists with the use of TIMI criteria (without knowledge of patients’ data). The TIMI flow grades have been defined previously.12 In brief, grade 0 perfusion is no antegrade flow beyond the point of occlusion; grade 1 is minimal incomplete perfusion of contrast medium around the clot; grade 2 (partial perfusion) is complete but delayed perfusion of the distal coronary bed with contrast material; and grade 3 (complete perfusion) is antegrade flow to the entire distal bed at a normal rate. In six cases of disagreement, final TIMI grade was determined by consensus of two radiologists. The exclusion of these six patients did not affect the conclusion of this study. Percent coronary diameter stenosis of the infarct-related artery was also quantified without knowledge of patients’ data through the use of a validated technique.
Collateral channels were graded in the initial coronary angiograms as follows: 0, no collaterals; 1, incomplete slow opacification in the distal vessel; 2, slow but complete opacification of the distal vessel; and 3, opacification of the distal vessel as well as the donor vessel. The right anterior oblique projections of baseline and late-stage left ventriculograms were analyzed by an angiographer who was blinded to patients’ data. Global left ventricular ejection fraction (LVEF) was determined by the area-length method, and regional wall motion (RWM) of the infarct zone (SD per chord) was determined by the centerline method.13
All data are expressed as mean±SD. Multiple comparisons were made with a one-way ANOVA, and individual data were compared with the use of Schéffe’s F test for factor analysis. Statistical analysis of temporal changes in certain variables was computed with the use of ANOVA and Schéffe’s F test for repeated measures. Differences were considered significant at P<.05.
Comparison Between TIMI Grades 2 and 3
Detailed review of cineangiograms revealed that 68 of 86 patients represented TIMI grade 3 reflow. The other 18 patients (21%) met TIMI grade 2 reflow criteria despite the absence of any residual coronary obstruction, apparent dissection, thrombosis, or distal vessel cutoff suggestive of macroembolization. No patient showed TIMI grade 0 or 1 patency after coronary recanalization. Patients’ characteristics were compared for those with TIMI grades 2 and 3 reflow (Table 1⇓). There were no differences in age, sex, culprit lesion, time from onset to reperfusion, or the residual stenosis between the two subsets. Preprocedural collateral grade was greater in those with TIMI grade 3 reflow than in those with TIMI grade 2 reflow. All of the patients with non–Q wave myocardial infarction met TIMI grade 3 criteria.
Left ventricular functional outcomes (WMS, LVEF, and RWM) were compared between those with TIMI grades 2 and 3 reflow (Fig 1⇓). There were no differences in baseline left ventricular performance between the two subsets other than WMS being slightly greater in TIMI grade 2 reflow. Patients with TIMI grade 3 reflow showed substantial improvement in left ventricular performance in the convalescent stage (WMS, 16±5 versus 10±7 [acute versus late]; LVEF, 44±13% versus 55±13%; RWM, −3.12±0.62 versus −2.24±0.93 SD/chord). In contrast, little or no temporal improvement was observed in those with TIMI grade 2 reflow (WMS, 19±3 versus 18±3; LVEF, 38±8% versus 40±8%; RWM, −3.35±0.40 versus −3.20±0.39 SD/chord). Thus, the late-stage left ventricular function was significantly better in patients with TIMI grade 3 reflow than in those with TIMI grade 2 reflow.
Microvascular Dysfunction and TIMI Flow Grade
MCE after coronary recanalization demonstrated significant contrast opacification within the risk area (MCE reflow) in 57 patients and substantial size of no reflow (MCE no reflow) in 29 patients. MCE showed reflow in 57 of 68 patients with TIMI grade 3 reflow (Fig 2⇓), whereas MCE showed no reflow in the other 11 patients with TIMI grade 3 reflow and in all of the 18 patients with TIMI grade 2 reflow (Fig 3⇓). Interestingly, MCE demonstrated no reflow regardless of apparently good radiocontrast run-off in the coronary angiogram in 11 patients (16%) (Fig 4⇓). Therefore, coronary angiographic TIMI grade 2 reflow is specific (100%) but not sensitive (62%) in predicting MCE no reflow.
Our patients were divided into three groups based on TIMI flow grades and the presence or absence of MCE reflow, TIMI grade 2 reflow (TIMI 2, 18 patients), TIMI grade 3 reflow but without MCE reflow (TIMI 3/MCE no reflow, 11 patients), and TIMI grade 3 reflow and MCE reflow (TIMI 3/MCE reflow, 57 patients). There were no significant differences in clinical characteristics among the three subsets, although angiographic collateral grade was greater in patients with TIMI 3/MCE reflow (Table 1⇑). Baseline left ventricular performance was better, improvement in left ventricular performance was larger, and, therefore, the late-stage left ventricular performance was far better in patients with TIMI 3/MCE reflow than in patients with TIMI 2 or TIMI 3/MCE no reflow (Table 2⇓). Thus, patients of TIMI 3/MCE no reflow were more like those with TIMI grade 2 reflow than those with TIMI 3/MCE reflow in terms of left ventricular performance.
Then, we compared the microvascular damage in the latter two groups. There was no significant difference in the size of MCE no reflow as assessed with the ratios to the risk area and to the left ventricular myocardium between patients with TIMI 3/MCE no reflow and patients with TIMI grade 2 (0.55±0.16 versus 0.62±0.19, P=NS; 0.31±0.11 versus 0.30±0.12, P=NS).
Although the TIMI flow grading is simple and intuitively appealing, it makes several assumptions relating visual assessment of angiographic contrast flow to perfusion at the myocardial tissue level. Differences among TIMI patency grades, however, have not been rigorously related to the severity of ischemic microvascular damage and functional outcomes. In this study, we compared MCE reperfusion patterns and left ventricular performance among different TIMI flow grades in patients with reperfused anterior wall myocardial infarction. To avoid the effect of vessel obstruction on TIMI flow grading, we selected the patients without apparent flow-restricting lesions after coronary angioplasty. After recanalization, 18 of 86 patients manifested TIMI grade 2 reflow despite no vessel obstruction, whereas the other 68 patients manifested TIMI grade 3 reflow. MCE data for all patients with TIMI grade 2 reflow indicate a substantial size of no reflow phenomenon within the risk area, whereas MCE demonstrated no reflow in only 16% of patients with TIMI grade 3 reflow. Early TIMI grade 3 reflow results in significantly better left ventricular functional outcome than does TIMI grade 2 reflow. Because early achievement of TIMI grade 2 reflow does not appear to lead to optimal myocardial salvage, acute interventions may be considered to be successful only when TIMI grade 3 reflow is achieved.
TIMI Grade 2 in Acute Myocardial Infarction
Slow filling of the epicardial coronary artery (TIMI grade 2 reflow) is uncommon after elective catheter intervention. Piana et al1 described the occurrence in only 2.0% of nearly 2000 consecutive percutaneous coronary interventions. The incidence is much higher, however, in patients undergoing intervention for acute myocardial infarction (11.5%) or treatment of the saphenous vein graft (4.0%). A similar phenomenon was described in another setting: catheter intervention of older saphenous vein grafts or native arteries in patients with unstable angina.2 14 In this study, antegrade coronary flow was determined to be TIMI grade 2 reflow in 18 of 86 patients (21%) with acute anterior wall myocardial infarction and without concomitant proximal epicardial obstruction (by clot, dissection, or spasm) or distal vessel cutoff after coronary angioplasty. This result implies that substantial reduction in postprocedural coronary flow is often found in patients with acute myocardial infarction.
However, there has been little convincing evidence to support the contention that TIMI grade 2 flow is caused by the severe microvascular dysfunction. Our MCE data showed a broad no reflow area in all patients with TIMI grade 2 reflow, whereas MCE reflow was obtained in the majority (84%) of patients with TIMI grade 3 reflow. Thus, broad and advanced microvascular perfusion abnormality is a main cause for postprocedural reduction in the epicardial coronary flow in patients with acute myocardial infarction.
The reduction in postprocedural coronary flow has been explained mainly by increased microvascular impedance to flow, which is caused by neutrophil plugging of capillaries, myocyte contracture and edema, distal microvascular spasm, and endothelial blistering.4 5 6 15 16 17 The magnitude of blood flow in a recanalized artery may also depend on several other complex, interrelated factors. Relevant variables of fluid dynamics include stenosis severity, which is negligible in the present study, and blood viscosity. Biological variables include myocardial mass supplied by the culprit artery, vasodilator reserve and duration of ischemia, the extent of reperfusion injury, cardiac preload and afterload, and timing of recanalization. Imperfect correlations between angiographic recanalization and tissue perfusion may be related to some of these factors as well as to technical problems of the TIMI grading system.
Implications of TIMI Grade 2
The TIMI study group initially designated patency grade 0 or 1 as thrombolysis failure and grade 2 or 3 as success, and TIMI grade 2 has been traditionally combined with TIMI grade 3 patency in the calculation of the total patency rate in the previous thrombolytic study.13 In contrast, the GUSTO angiographic investigators demonstrated that ventricular function was worse and mortality was higher among patients with TIMI grade 2 than among patients with complete reperfusion (TIMI grade 3).18 Recent GUSTO-1 trials documented that only TIMI grade 3 (but not grade 2) was associated with mortality reductions after acute myocardial infarction and indicated that TIMI grade 2 may not be regarded as success of reperfusion therapy.19 In addition, the PAMI study group reported that immediate percutaneous transluminal coronary angioplasty, which is associated with a higher patency rate than intravenous tissue-type plasminogen activator, reduces the combined occurrence of nonfatal reinfarction or death compared with tissue-type plasminogen activator therapy for acute myocardial infarction.20 Recently, Morishima et al21 demonstrated that angiographic no reflow after coronary intervention is a predictor of poor functional outcome in patients with acute myocardial infarction. Our data also documented that the early TIMI grade 3 reflow resulted in significantly better left ventricular functional outcome compared with TIMI grade 2 reflow. Thus, TIMI grade 2 caused by the most extensive microvascular dysfunction is associated with the advanced myocardial injury and therefore should be a marker of less favorable functional outcome. If only TIMI grade 2 reflow is achieved after all the effort to remove vessel obstruction, optimal myocardial salvage should be unlikely in the chronic stage.
There are at least three possible reasons for the failure of TIMI grade 2 reflow to lead to optimal myocardial salvage. First, microvascular dysfunction is a main cause of TIMI grade 2 reflow as previously mentioned. Ischemic episodes often break down the coronary microvasculature as well as myocardial cell. The no reflow phenomenon is always found in the center of myocardial necrosis and should be a sign of poor functional outcome.4 5 Second, TIMI grade 2 reflow may be inadequate to meet the metabolic demand of the jeopardized myocardium, falling below the critical threshold required to relieve ischemia of the myocardium. The third possible reason is the rethrombosis or the collapse of the postintervention lesion due to flow stagnation. In the other study, however, we found no difference in frequencies of coronary reocclusion between patients with and those without MCE reflow (3% versus 6%, respectively, P=NS).22
TIMI flow grade is influenced not only by microvascular dysfunction but also by epicardial coronary stenosis; therefore, coronary flow may decrease in patients with relatively preserved microvasculature if residual stenosis is critical. In such cases, left ventricular function may improve in the convalescent stage. Thus, if residual coronary stenosis is present after thrombolysis, TIMI grade 2 reflow does not necessarily indicate microvascular dysfunction. Additional MCE may be particularly helpful in such patients.
TIMI Grade 3
The degree of left ventricular functional improvement varied even among the patients representing good radiocontrast run-off (TIMI grade 3 reflow). Although the majority of patients with TIMI grade 3 reflow showed good MCE reflow, a substantial size of MCE no reflow was observed in 16% of this group. Temporal left ventricular functional improvement was worse in these patients than in those with MCE reflow in TIMI grade 3. Although TIMI grade 3 reflow generally indicates better myocardial perfusion and conveys better outcomes than TIMI grade 2 reflow, it does not always guarantee the successful myocardial reperfusion and functional improvement in individual patients. Additional MCE is particularly valuable in patients with TIMI grade 3 reflow because of its ability to detect microvascular damage, which is observed in some of this group.
Despite the presence of the no reflow phenomenon, some patients showed good radiocontrast run-off (TIMI grade 3) and the other patients showed slow radiocontrast opacification (TIMI grade 2). We initially speculated that the ischemic microvascular damage would be more severe in patients with TIMI grade 2 reflow than in those with TIMI grade 3 reflow, even among the patients with MCE no reflow. Although not statistically significant, late-stage left ventricular performance was slightly worse in patients with TIMI 2 than in those with TIMI 3/MCE no reflow. Therefore, patients with TIMI 3/MCE no reflow may be regarded as the intermediary group.
The size of the no reflow phenomenon, however, did not differ between these two subsets. Several possible reasons are postulated, including size (length) of the coronary artery; hemodynamic variables including heart rate, blood pressure, and left ventricular filling pressure; and the timing of evaluation. Hyperemic response and microvascular dysfunction exist within the risk area immediately after reflow, and their balance may vary with time for several hours after reperfusion.23 Other factors, such as reproducibility of TIMI grading and variables that may influence coronary flow dynamics, should also be taken into consideration in the evaluation of angiographic findings.
Critique of Methods
There were several limitations in this retrospective study. Although possibilities of mechanical obstruction were excluded on the basis of catheterization and clinical reports and were confirmed by the review of the cineangiograms, there was a potential for bias. TIMI flow grades were assessed retrospectively, although two radiologists reviewed the films to reduce potential bias in these measurements. TIMI flow grade is only a surrogate for direct measurement of coronary blood flow, and the influence of oxygen consumption, hemodynamic variables (heart rate and blood pressure), size of coronary artery, and local autoregulation cannot be excluded.
MCE results should also be considered in light of several limitations to the analysis. First, our method is largely dependent on echocardiographic image quality. Second, contrast intensity is influenced by many factors, including the size and number of microbubbles and factors altering ultrasonic reflection such as gain setting, depth of penetration, incident angle, axial and lateral resolution, gray-scale compression, and the nonlinearity of echo amplitude signals. Finally, the size of the no reflow phenomenon may alter with time after reperfusion.24 In a study in dogs, Villanueva et al23 reported that the size of residual contrast defects usually reaches its maximal value at 15 minutes after coronary reflow, which is similar to our timing of examination.
Although the success or outcome of coronary intervention should be ideally assessed with a parameter of myocardial perfusion, the major end point of many angiographic trials has been the acquisition of a patent infarct-related artery. Our results clearly showed the values and limitations of coronary angiography in the evaluation of myocardial salvage. Because the patency status of the infarct-related artery does not indicate the extent of microvascular integrity, assessment of microvascular perfusion may be essential in gaining further understanding of patient outcomes and the relation between interventions and outcomes. In this context, TIMI grade 2 reflow, despite no epicardial flow–restricting lesion, is a specific, although not sensitive, indicator of incomplete myocardial perfusion, and “recanalization” does not always mean “reperfusion.” Thus, we can easily differentiate the patients with poor left ventricular functional outcomes in the catheter laboratory just after coronary recanalization.
Our data also showed that MCE, which is used to visualize tissue perfusion at the microvascular level, is more sensitive to detect microvascular damage or dysfunction in the infarct region than is conventional coronary angiography. Additional MCE provides a better understanding of myocardial perfusion in those who manifested good radiocontrast dynamics. The precise information on the postischemic microvascular conditions (and, thus, myocardial viability) should aid in assessing size of infarction and thereby in making decisions regarding therapeutic strategy in the early stage of infarction.
The authors greatly acknowledge the excellent technical assistance of Yuzo Sakagami, Masakazu Ueda, and Naoki Jonishi and the excellent secretarial assistance of Rie Nishizawa.
- Received August 1, 1995.
- Revision received November 27, 1995.
- Accepted December 6, 1995.
- Copyright © 1996 by American Heart Association
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