Temporal Changes in Myocardial Perfusion Patterns in Patients With Reperfused Anterior Wall Myocardial Infarction
Their Relation to Myocardial Viability
Background Several studies demonstrated ischemic microvascular damage in patients with acute myocardial infarction (AMI). In this study, myocardial contrast echocardiography (MCE) was used to assess the temporal changes in myocardial perfusion after reflow and to investigate the relation between MCE findings and myocardial viability.
Methods and Results MCE was performed with the intracoronary injection of sonicated microbubbles before and shortly after coronary reflow and 1 month later in 45 patients with anterior wall AMI. MCE before reflow was analyzed to determine the risk area as an area of contrast defect in the apical long-axis view. MCE images after reperfusion were analyzed to determine peak contrast intensity, which should be in proportion to the concentration of microbubbles within the microvasculature and in the infarcted and normal myocardium, and the ratio of these (PI ratio) was used to assess microvascular integrity. Areas of residual contrast defect were expressed as a ratio to those of left ventricular myocardium (RCD ratio) to assess the spatial extent of the MCE “no reflow.” Regional wall motion (RWM, SD per chord) in the territory of the left anterior descending coronary artery was determined by the centerline method in both the acute and late stages. Although the PI ratio was extremely low shortly after coronary reflow, it increased in the late stage of AMI with the improvement in regional contractile function (RWM, −3.2±0.5 versus −2.6±1.0, P<.01; PI ratio, 0.44±0.25 versus 0.60±0.29, P<.01). Reduction in the RCD ratio was observed even in 15 patients with MCE no reflow in the acute stage (0.33±0.09 versus 0.16±0.11, P<.01). Then we investigated the relation between residual contractile function and microvascular integrity in the late stage. A significant correlation was found between the PI ratio and RWM (r=.73, P<.001) in the late stage of the AMI.
Conclusions (1) Recovery from ischemic microvascular damage is generally observed in the late stage of AMI in association with improvement in myocardial contractile function. The degree of improvement in contractile function and microvascular integrity, however, varies among patients. (2) Contrast peak intensity in the late stage of infarction may provide a useful estimate of myocardial viability.
Coronary intervention is widely performed for restoring coronary flow to the jeopardized myocardium in patients with acute myocardial infarction. Although it is generally believed that a patent epicardial coronary vessel should guarantee flow at the microvascular beds, ischemic episodes may often break down the coronary microvasculature, and therefore, flow to the infarcted myocardium may be markedly reduced despite angiographic documentation of reflow in the infarct-related artery.1 2 3 4 5
Spatial distribution of myocardial blood flow is visualized with myocardial contrast echocardiography (MCE), which is a promising method to evaluate the degree and extent of microvascular dysfunction.6 7 8 9 We previously demonstrated that myocardial perfusion to the infarct area is absent or extremely low shortly after coronary reflow in about one quarter of patients with acute myocardial infarction and that recovery of myocardial contractile function is worse in patients without MCE reflow than in those with MCE reflow.10 Although myocardial perfusion shortly after coronary reflow has been clarified, little is known about its changes in the convalescent stage. Previous studies indicated that ischemic microvascular damages may be reversible11 or progressive12 13 after coronary reflow.
In this study, microvascular function was assessed with MCE on the day of infarction and 4 weeks later in patients with reperfused anterior wall myocardial infarction. Corrected myocardial video intensity and the extent of no or extremely low reflow area were compared between acute- and chronic-stage MCE to elucidate whether the ischemic microvascular damage is reversible. We also studied the relation between corrected myocardial video intensity, which is considered to be reduced with a decrease in intact microvessels, and residual contractile function to clarify whether myocardial viability can be assessed with MCE shortly after coronary reflow or in the chronic stage.
MCE was performed in 51 consecutive patients admitted to the coronary care unit of Sakurabashi Watanabe Hospital between September 1991 and July 1993 for an acute myocardial infarction of the anterior wall. They underwent intracoronary thrombolysis and/or coronary angioplasty to the totally or subtotally occluded infarct-related artery (Thrombolysis in Myocardial Infarction Trial [TIMI] grade 0 or 1) within 6 hours of the onset of chest pain and achieved successful coronary reflow. 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 a greater than threefold increase in serum creatine kinase activities. Six patients were excluded from analysis because of inadequate image quality (3 patients), multivessel disease (1 patient), inadequate coronary reperfusion (TIMI grade 0, 1, or 2) (1 patient), and ischemic event during the follow-up period (1 patient). Therefore, this report is based on the remaining 45 patients (33 men and 12 women; mean age, 55 years; range, 38 to 75 years) in whom successful reflow was achieved with intracoronary thrombolysis (tissue plasminogen activator 1 200 000 U) (6 patients) or angioplasty (39 patients). Thirty-eight patients subsequently developed Q waves in the 12-lead surface ECG, and the other 7 patients manifested nonQ-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 the femoral approach on the day of infarction. Each patient rested in the supine position. On completion of diagnostic coronary arteriography and left ventriculography, 2 mL of sonicated Ioxaglate (Hexabrix-360, Tanabe) containing microbubbles (mean size, 12 μm) was injected into the left coronary artery for MCE.10 A commercially available mechanical sector scanner (model SAL-38B, Toshiba; carrier frequency, 3.5 MHz) was used. Imaging of the apical long-axis view was initiated about 10 seconds before 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 contrast injection into the right coronary artery a mean of 16 minutes (10 to 24 minutes) after successful reflow was confirmed in coronary arteriograms. Lead II ECG was continuously monitored during and after MCE.
Coronary arteriography, left ventriculography, and MCE were repeated at a mean of 25 days after the infarction (24 to 29 days) by the right brachial approach. MCE was done in the same fashion as in the acute stage.
Analysis of MCE Data
Echocardiographic images were analyzed with a commercially available off-line computer system (model LA-500, PIAS). End-diastolic echocardiographic frames after contrast injection were selected with synchronization to the peak of the R wave on the ECG. Echocardiographic images with the best delineation between contrast-enhanced and nonenhanced myocardium were selected by an operator to determine the risk area, which was determined as an area showing no contrast enhancement in prereflow MCE of either right or left coronary artery injection. We measured the endocardial lengths of the ventricular septal and the posterior wall segments showing contrast enhancement to identify the risk area in the follow-up study.
For analysis of MCE images after coronary reflow, end-diastolic images of the left ventricle were digitized in a 256×256 matrix for 10 consecutive cycles with 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 analyses. Qualitative and quantitative analyses were performed for the assessment of regional microvascular damage. When the endocardial length of the area showing contrast defect exceeded one half that of the segment length, myocardial reperfusion in the corresponding segment was considered incomplete. Areas showing contrast defects are always clearly defined, and measurements of the size of the residual contrast defect are highly reproducible, as mentioned in our previous study.10
Identification of the risk area in the postreflow MCE images was done with reference to the predetermined endocardial length showing contrast enhancement before reflow. From MCE images before coronary reflow, we measured the endocardial length of the “positive” contrast segments from the cardiac base both in the posterior wall and in the ventricular septum. The other segments showing “negative” contrast compose the risk area. In MCE images after coronary reflow, we identified the initial risk area after determining the extent of segments showing positive contrast before coronary reflow by referring the predetermined lengths. Excluding the endocardial and epicardial borders, we measured contrast peak intensity of the entire myocardial segment. We determined corrected contrast intensity (the baseline contrast intensity subtracted from the peak values in gray scale, units per pixel) in the risk area and in the normal posterior wall, and the ratio of these (PI ratio) was used for assessing the integrity of coronary microvasculature. The extent of the no-reflow area was assessed with the ratio of the area showing residual contrast defect after coronary reflow to the area of the total left ventricular myocardium (RCD ratio). These parameters were also measured in the chronic-stage study.
Analysis of Catheterization Data
The right anterior oblique views of left ventriculograms obtained in the initial and delayed studies were used for the assessment of regional left ventricular function. Regional wall motion was assessed with the centerline method using a 100-chord model. The shortening fraction of each chord was normalized to the end-diastolic perimeter of the left ventricle. This normalized wall motion in the perfusion territory of the left anterior descending coronary artery (chords 10 through 66) was expressed as SDs from the normal value, which was previously determined as a mean value among 38 age-matched healthy subjects (regional wall motion, SD per chord).14
Collateral channels were graded in the initial coronary arteriography 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. Cine films were analyzed in a random sequence by an angiographer who was blinded to patient data.
Reproducibility of Data
The reproducibility of measuring the contrast intensity and areas of residual contrast defects was assessed by repeating MCE in 5 patients. Percent absolute difference between the two trials was 6.3±4.5% for the contrast intensity and 4.8±2.6% for the area of residual contrast defects. Intraobserver and interobserver variabilities were determined by measuring the contrast intensity in 10 randomly selected records twice by the same observer and by two independent observers who were blinded to patient data as well as to the results from the other observer. Intraobserver and interobserver variabilities of peak contrast intensity were 4.2±4.0% and 5.1±4.2% (absolute difference), respectively. Intraobserver and interobserver variabilities of areas of residual contrast defects were 4.2±3.2% and 4.7±2.4% (absolute difference), respectively.
All data are expressed as mean±SD. Statistical analysis of changes in PI ratio and RCD ratio was computed by ANOVA and Scheffé’s F test for repeated measures. When two different groups were compared for certain variables, a one-way ANOVA and Scheffé’s F test for factor analysis were applied. Differences were considered significant at P<.05.
No patients showed significant progression of coronary stenosis in the infarct-related artery (residual stenosis <75%) or in the other coronary arteries. No ischemic event was observed during the follow-up period in each patient.
Changes in Myocardial Perfusion After Coronary Reflow
Fig 1⇓ shows myocardial perfusion patterns before and shortly after reflow and 4 weeks later. This patient had preseptal occlusion and achieved coronary reflow 4.5 hours after the onset of infarction. Before coronary reflow, a contrast defect indicating risk area was evident in the ventricular septum and cardiac apex in the MCE of left coronary artery injection. After coronary reflow, contrast enhancement was observed in the risk area; however, the contrast intensity was lower in the risk area than in the posterior wall. Significant contrast enhancement was also obtained in the risk area 4 weeks later, but the contrast intensity was still lower in the risk area than in the posterior wall. Fig 2⇓ shows temporal changes in regional myocardial perfusion in the patient who had postseptal occlusion and achieved coronary reflow by angioplasty 4.3 hours after the onset of infarction. Shortly after coronary reflow, residual contrast defect extended from the distal ventricular septum to the cardiac apex. The area of residual contrast defect was reduced in 4 weeks in this patient.
Contrast enhancement was observed within the risk area in MCE performed shortly after coronary reflow in 30 of 45 patients studied. Significant amounts of residual contrast defect, indicating the no reflow phenomenon, were observed in the other 15 patients. There were no differences in age, sex, history of hypertension, history of diabetes, time from the onset of infarction to reperfusion, collateral grade, or selection of reperfusion treatment between the two subsets (Table⇓). All patients with the no reflow phenomenon subsequently developed Q waves in 12-lead surface ECGs. In 30 patients without this phenomenon, 7 patients (23%) manifested nonQ-wave myocardial infarction and the other 23 manifested Q-wave myocardial infarction.
Fig 3A⇓ illustrates temporal changes in the values for the PI ratio. Shortly after coronary reflow, values for the PI ratio were lower than unity, indicating that the microbubble concentration, which is in proportion to regional microvascular density, is lower in the infarct area than in the normal region. The PI ratio increased as a whole from the acute to the late stage (0.44±0.25 versus 0.60±0.29, P<.01); however, if we looked at the individual patients, the values for the PI ratio did not change uniformly. The PI ratio increased from the acute to the late stage even in the subset of patients with no reflow in postreflow MCE (0.20±0.06 versus 0.32±0.14, P<.001); however, the PI ratio was significantly (P<.01) lower in these patients than in those with MCE reflow in both the acute and the late stages. Mean PI ratio also increased in the convalescent stage in patients with MCE reflow (0.56±0.21 versus 0.73±0.24, P<.01), but a decrease in the PI ratio was observed in 7 patients. Regional wall motion in the late stage was better in those in whom the PI ratio increased than in those in whom the PI ratio decreased (−1.95±0.98 versus −2.96±0.52 SD per chord, P<.05).
To clarify whether the area showing no reflow decreases in the convalescent stage, we assessed temporal changes in the RCD ratio in 15 patients without MCE reflow (Fig 3B⇑). The RCD ratio decreased significantly from the acute to the late stage (0.33±0.09 versus 0.16±0.11, P<.01), indicating that the area showing no reflow decreases in 1 month. Conversely, residual contrast defect was observed in the late stage only in 3 of the patients with MCE reflow. In these 3 patients, values for the RCD ratio were 0.10, 0.11, and 0.15, and their PI ratios were reduced in the late stage.
Integrity of Microvasculature and Myocardial Viability
Regional wall motion in the territory of the left anterior descending coronary artery was improved from the acute to the late stage as a whole (−3.21±0.48 versus −2.56±0.99 SD per chord, P<.01) (Fig 3C⇑). However, there was great variability in the change among patients. The regional wall motion in the late stage was more depressed in the patients with MCE no reflow compared with those with MCE reflow (−3.33±0.37 versus −2.20±0.99 SD per chord, P<.01).
The relation between myocardial viability and the integrity of microvasculature was examined. There was a rough correlation between the PI ratio shortly after reflow and late-stage myocardial contractile function (r=.46, P<.01) (Fig 4A⇓). Patients with MCE no reflow indeed had lower PI ratios at day 1 and more depressed regional wall motion at day 28 than those with MCE reflow. However, the improvement in regional wall motion was not necessarily observed in patients with MCE reflow. These data suggest that late-stage myocardial contractile function cannot be predicted successfully from the PI ratio shortly after reflow. In contrast, there was a significant relation between the PI ratio in the late stage and the regional wall motion in the late stage (r=.73, P<.0001) (Fig 4B⇓), irrespective of the inclusion or exclusion of the patients with MCE no reflow in the acute stage. These results indicate that we may evaluate myocardial viability by analysis of the regional contrast gray level intensity in the chronic stage of infarction.
Temporal changes in regional myocardial perfusion after coronary reflow were assessed with serial MCE studies in patients with acute anterior wall myocardial infarction to clarify the relation between microvascular function and myocardial viability. Shortly after reflow, the peak contrast intensity was lower in the infarct segment than in the normal segment. The perfusion defect, implying impairment in microvascular function, was observed in 33% of the patients studied. Although the impaired microvasculature improved its integrity within 1 month after reperfusion, the degree of improvement as assessed with the change in the PI ratio varied among patients. A close relation was found between the PI ratio and regional wall motion in the late stage, implying that interindividual variability in the PI ratio can be explained by the differences in the amount of residual myocardium. Thus, although the microvasculature is impaired in the acute stage of the infarction, it generally improves within 1 month after reperfusion. In addition, the regional peak contrast intensity in the late stage of infarction seems to be a useful estimate of myocardial viability.
Microvascular Damages After Reperfusion
It is well known that myocardial infarction is associated with an impairment in microvascular function or integrity, although the degree of impairment differs among patients. There are no appropriate parameters, however, to characterize microvascular impairment in humans. In this study, we measured two parameters, PI ratio and RCD ratio, to characterize the microvascular damage. The RCD ratio was used to quantify the spatial extent of no or extremely low myocardial perfusion. The PI ratio was used to assess coronary microvascular integrity because peak contrast intensity is in proportion to the concentration of microbubbles contained in the microvasculature and because the density of the intact microvessels should be a major determinant of the concentration of microbubbles. If the same contrast medium is injected into both normal and infarcted myocardium, the contrast gray intensity should be lower in the infarcted myocardium than in the normal myocardium, reflecting the proportion of the density of intact microvessels and hence the amount of viable myocardium. In this study, the peak intensity in the infarct area was expressed as a ratio to that in the posterior wall to correct for the interindividually variable echo attenuation.
Shortly after coronary reflow, substantial perfusion defects were observed in 33% of the patients studied. In addition, the mean PI ratio was 0.44, indicating that the microvasculature should be less dense in the infarct region compared with the normal region. This result indicates the presence of microvascular injury shortly after reperfusion in patients with acute myocardial infarction and is in agreement with the results of experimental models.15 16 17 18
Our MCE findings clearly demonstrate the dynamic nature of postischemic myocardial perfusion, which had not been characterized in patients. In patients with MCE no reflow, the spatial extent of the no-reflow area was reduced and the PI ratio increased in the late stage of infarction. Myocardial staining with contrast medium usually appears from the basal segment of the initial perfusion defect. We did not find a progression in the spatial extent of the area of MCE no reflow in the convalescent stage, implying that microvascular damage may be at least partially reversible even in the area of MCE no reflow. However, the PI ratio was still lower in the area of MCE no reflow than in the area with MCE reflow, indicating the presence of breakdown of the microvessels in the area of MCE no reflow. Little or no improvement in regional function was observed in these patients, as also documented in our previous study.10 These data imply that improvement in myocardial perfusion in patients with MCE no reflow may be dissociated from improvement in regional contractile function.
Temporal changes in myocardial perfusion were even more complicated in patients with MCE reflow than in those with MCE no reflow. Temporal changes in the PI ratio varied among the patients. In 23 (77%) of 30 patients with MCE reflow, the PI ratio increased from the acute to the late stage, indicating improvement in microvascular function and/or an increase in the density of microvasculature in the infarct myocardium. These data suggest that postischemic dysfunction of the microvasculature is partially reversible in the majority of patients with MCE reflow. In a canine experiment, Bolli et al19 and Triana and Bolli20 documented that reversible ischemic insult causes prolonged microvascular dysfunction, that is, an increase in resting vascular resistance and an impairment in vasodilator responsiveness. They called this phenomenon microvascular “stunning.” This phenomenon may partially explain the reversibility of microvascular function in humans.
A decrease in PI ratio, however, was observed in the late stage in 7 patients (23%) with MCE reflow, suggesting that progressive dysfunction of the microvasculature is still possible even after reperfusion. In 3 of these patients, areas of no reflow appeared within the infarct area in the late stage. We could not clarify the underlying mechanisms in this study; however, two mechanisms are noted. First, sustained hyperemia in the infarct bed after coronary reflow is noted. We might underestimate the degree of myocardial necrosis and overestimate the degree of myocardial salvage if only contrast enhancement were used as a marker of viable myocardium.17 21 22 Alternatively, coronary microvascular damage may progress for several hours after coronary reflow.11 12 If so, microvascular integrity might be overestimated from the PI ratio determined shortly after coronary reflow.
Microvascular Integrity and Myocardial Viability
Several groups have shown the close relation between myocardial blood flow or coronary microvascular integrity and myocardial viability. Dwyer et al23 showed that the clearance rate of 133Xe correlated with myocardial perfusion in multiple areas of the heart in patients with myocardial infarction. They demonstrated that myocardial perfusion is reduced in regions of transmural infarction. Baer et al24 used single-photon positron emission tomography to document a reduction in myocardial perfusion in regions of transmural myocardial infarction. Vanoverschelde et al5 studied the relation between myocardial oxidative metabolism and myocardial blood flow using positron emission tomography in the convalescent stage of myocardial infarction and showed that regional oxidative metabolism is reduced in proportion to residual myocardial blood flow.
In this study, we hypothesized that myocardial viability may be evaluated with MCE by measuring regional contrast gray intensity. Because the contrast gray intensity is considered to change with bubble concentration in the microvasculature and because a reduction in the amount of the myocardium should be associated with sparse vascular density, a decrease in contrast gray intensity in the infarcted myocardium should reflect the reduced amount of residual myocardium. Therefore, the PI ratio was used to assess regional myocardial viability in this study.
We first investigated whether late-stage myocardial function can be predicted from the acute-stage PI ratio. There was a rough correlation between the PI ratio at day 1 and late-stage regional wall motion. This result indicates that we cannot successfully predict late-stage myocardial function simply with the acute-stage PI ratio. However, the acute-stage PI ratio was low and late-stage regional wall motion was depressed in patients with MCE no reflow, as shown in our previous study.
In contrast to the PI ratio at day 1, there was a significant correlation between the PI ratio in the late stage and late-stage regional wall motion. These data imply that the infarct myocardium with poor contractile function despite the patent coronary supply represents no or low contrast enhancement. In other words, the residual contractile function of the myocardium, which should be in proportion to the amount of viable myocardium, is related to the degree of MCE enhancement. These results agree with our hypothesis. Thus, we may extend the potential of MCE to the evaluation of regional myocardial viability in patients with myocardial infarction when the evaluation is done after the acute pathological responses to ischemia and reperfusion have been established.
Several mechanisms may be considered to explain the findings that late-stage regional wall motion correlated better with the late-stage PI ratio than with the acute-stage PI ratio and that the PI ratio in the late stage is very different from that in the acute stage. These may be most appropriately explained by the temporal changes in myocardial perfusion patterns even after coronary reperfusion. Villaneuva et al18 observed similar findings in dogs. In dogs with sustained hyperemia or progressive microvascular damages after reperfusion, microvascular integrity may be overestimated from the acute-stage PI ratio. Conversely, if recruitment of coronary microvasculature occurred, the late-stage microvascular integrity might be underestimated from the acute-stage PI ratio.
Critique of Our Methods
Although changes in peak contrast intensity appear to reflect regional vascular density, this index does not by itself provide absolute estimates of regional vascular density. Contrast intensity is influenced by many other factors, including the size and number of microbubbles and factors that alter 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. Thus, one must use the same view and gain settings when assessing temporal changes in peak intensity. In addition, to minimize interindividual variability of echo reflections and variability of bubble production, the peak contrast intensity in the risk area was determined as a ratio to that in the posterior wall in each stage.
In this study, we analyzed the relation between the PI ratio and regional wall motion using linear regression analysis. The relation, however, may not be linear. Further studies are required to establish the regression curves between these two variables.
The contrast intensity of the posterior wall was used as a reference in this study. Therefore, our method may not be applied to patients with multivessel disease and/or recurrent myocardial infarction because the contrast intensity in the normal segment may not be accurately determined in these patients.
Wall motion may be an inadequate index of myocardial viability: akinesis does not necessarily imply scar. Cigarroa et al25 documented that 40% of akinetic segments in multivessel diseases exhibit contractile reserve by dobutamine stress echocardiography. However, the concept of “stunning” or “hibernating” is not relevant to the main theme of the present study. In addition, we excluded the patients with critical residual stenosis and assessed wall motion a month after the onset. In the chronic setting, the presence of akinesis is more likely to reflect irreversible dysfunction or scar than stunning or hibernation.26
In a recent canine study, Villaneuva et al18 demonstrated that MCE in conjunction with intravenous dipyridamole is a promising method in the identification of the spatial extent of myocardial necrosis. Although we have not done such interventions, their method may augment the potential of MCE in the assessment of myocardial viability in humans.
Despite the limitations of the present technology, MCE provides useful information on the condition of coronary microvasculature in the early and convalescent stages of myocardial infarction in humans. The impairment in the microvasculature can be detected as a reduction in the corrected peak intensity relative to that in the normal region and the appearance of MCE no reflow. In addition, the findings of this study demonstrated the potential clinical value of MCE in the evaluation of myocardial viability in patients with myocardial infarction. The area of myocardial infarction is characterized by reduced peak contrast intensity, and peak contrast intensity seems to be inversely related to myocardial viability.
MCE is inexpensive and can be performed in the catheterization laboratory with some additional time. It may also provide useful information about estimation of myocardial viability. Sonicated albumin solution has potential to produce contrast enhancement of the left-side chambers as well as the myocardium through contrast injection into the right atrium27 or peripheral veins. Such new contrast media should expand the clinical application of MCE. With the advent of such contrast media, MCE may be performed to serially assess myocardial flow and viability after coronary reperfusion at bedside in the intensive care or coronary care unit.
The authors gratefully acknowledge the excellent technical assistance of Yuzo Sakagami and Masakazu Ueda and excellent secretarial assistance of Rie Nishizawa.
- Received July 6, 1994.
- Accepted September 23, 1994.
- Copyright © 1995 by American Heart Association
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