Determinants of Myocardial Salvage During Acute Myocardial Infarction

Transcription

1 JACC: CARDIOVASCULAR IMAGING VOL. 3, NO. 5, BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN X/$36. PUBLISHED BY ELSEVIER INC. DOI:1.116/j.jcmg Determinants of Myocardial Salvage During Acute Myocardial Infarction Evaluation With a Combined Angiographic and CMR Myocardial Salvage Index José T. Ortiz-Pérez, MD, Daniel C. Lee, MD, Sheridan N. Meyers, MD, Charles J. Davidson, MD, Robert O. Bonow, MD, Edwin Wu, MD Chicago, Illinois OBJECTIVES This study examined the contribution of symptom-to-reperfusion time, collateral flow, and antegrade flow in the infarct-related artery on myocardial salvage using a combined angiographic cardiac magnetic resonance (CMR) method. BACKGROUND The myocardium supplied by an acutely occluded artery defines the anatomical area at risk for infarction. This area can be determined independently of residual coronary flow to the risk region. Moreover, the difference between this area and infarct size constitutes viable myocardium that has been salvaged. METHODS In 121 subjects presenting with ST-segment elevation myocardial infarction revascularized by primary percutaneous intervention, the angiographic anatomical area at risk was retrospectively measured using the Bypass Angioplasty Revascularization Investigation Myocardial Jeopardy Index (BARI score). Within 1 week, CMR was performed in the entire cohort and repeated in 89 subjects at 5 3 months to determine infarct size and wall motion recovery. The myocardial salvage index (MSI) was computed as (BARI score infarct size)/left ventricular mass. RESULTS The MSI was negligible in patients with Thrombolysis In Myocardial Infarction (TIMI) flow grade 1, absent collateral vessels, and 4 h of symptom-to-reperfusion time, as compared with patients with TIMI flow grade 1 or existent collateral vessels (.2 1. vs , p.1). The initial TIMI flow grade, time to reperfusion, presence of microvascular obstruction, and collateral flow were found to be independent predictors of MSI and infarct transmurality (p.5 for both). The BARI score was only predictive of MSI (p.1). The MSI correlated inversely with wall motion score at baseline (R.27, p.1) and at follow-up (R.38, p.1). Infarct transmurality also correlated with wall motion score at baseline (R.52, p.1) and at follow-up (R.58, p.1). Increasing MSI (p.1) and decreasing infarct transmurality (p.1) were associated with an improvement in wall motion and prognosis. CONCLUSIONS Early mechanical reperfusion and maintenance of antegrade or collateral flow independently preserves myocardial salvage primarily through a reduction in infarct transmurality. This novel integration of coronary angiography and CMR techniques to quantify myocardial salvage predicts functional recovery and improved prognosis. (J Am Coll Cardiol Img 21;3:491 5) 21 by the American College of Cardiology Foundation From the Feinberg Cardiovascular Research Institute and Division of Cardiology, Northwestern University Feinberg School of Medicine, and the Bluhm Cardiovascular Institute, Northwestern Memorial Hospital, Chicago, Illinois. This work was supported by a grant from the American Heart Association Scientist Development Grants (Dr. Wu), the GlaxoSmithKline Research and Education Foundation for Cardiovascular Disease (Dr. Wu), the Department of Medicine, and the Feinberg Cardiovascular Research Institute of Northwestern University. The Working Group on Ischemic Cardiomyopathy of the Spanish Society of Cardiology supported Dr. Ortiz-Pérez. Manuscript received June 3, 29; revised manuscript received January 11, 21, accepted February 2, 21.

2 492 JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 5, 21 ABBREVIATIONS AND ACRONYMS ANOVA analysis of variance BARI Bypass Angioplasty Revascularization Investigation Myocardial Jeopardy Index CMR cardiac magnetic resonance ECG electrocardiogram EF ejection fraction IRA infarct-related artery LV left ventricle/ventricular MACE major adverse cardiac events MSI myocardial salvage index PCI percutaneous coronary intervention TIMI Thrombolysis In Myocardial Infarction WMS wall motion score Maintenance of myocardial viability is the goal of reperfusion therapy during acute myocardial infarction. Myocardial salvage, defined as the amount of myocardium that is jeopardized by a coronary occlusion but spared from infarction, can be used to compare different treatment options so that strategies that show a benefit in salvage could be implemented in clinical practice. For a given acute coronary artery See page 51 occlusion, factors other than reperfusion therapy modulate infarct size. These include the duration of the occlusion and the presence of residual flow to the territory at risk, via either collateral vessels or antegrade flow through the infarct-related artery (IRA) (1). When measuring myocardial salvage attributed to the presence of residual flow or to the reperfusion therapy, appropriate adjustment for the size of jeopardized myocardium is required. In a population with an occluded IRA, we previously demonstrated that quantitatively scoring coronary angiograms using a modification of the Bypass Angioplasty Revascularization Investigation Myocardial Jeopardy Index (BARI score) can accurately determine the area at risk for infarction (2). Moreover, by additionally using information from contrast-enhanced cardiac magnetic resonance (CMR) imaging to delineate acute infarct sizes, we investigated the impact of collateral vessels and time to reperfusion on the degree of salvage in patients with ST-segment elevation myocardial infarction (STEMI). In the current investigation, we expanded this combined angiographic CMR method to evaluate the additional impact of patent antegrade flow through the IRA on salvage and extended the importance of this novel index of myocardial salvage to predict left ventricular (LV) segmental wall motion recovery on follow-up. METHODS Study population. We enrolled patients admitted to Northwestern Memorial Hospital for primary percutaneous coronary intervention (PCI) with their first myocardial infarction in a prospective study evaluating LV remodeling (3). Patients with ventricular arrhythmias, pacemakers, defibrillators, or hemodynamic instability and patients who refused to undergo a baseline or follow-up CMR were excluded. For the purpose of this retrospective analysis, we included subjects who met the following criteria: 1) no prior history or electrocardiographic evidence of myocardial infarction; 2) more than 3 min of chest pain; 3) electrocardiographic ST-segment elevation.1 mv in at least 2 adjacent leads or patients in whom the electrocardiogram (ECG) suggested true posterior infarction; 4) PCI of the IRA within 24 h from symptom onset; and 5) a CMR performed within the first week after admission. Among the 127 patients identified, we excluded 1 subject with previous coronary bypass surgery, 2 subjects treated with fibrinolytic therapy, 1 subject with uncertain identification of the IRA, and 2 patients who were unable to complete the initial CMR due to claustrophobia. Eighty-nine subjects from our previous publication, which initially described the methodology in assessing the area at risk and myocardial salvage, were included in the current analysis. This previous publication also evaluated the roles of the duration of occlusion and collateral flow on myocardial salvage in patients presenting with completely absent antegrade flow in the culprit vessel (Thrombolysis In Myocardial Infarction [TIMI] flow grade only) (2). For the current report, we further expanded this analysis to include a broader scope of patients with an acute myocardial infarction. An additional 28 subjects with TIMI flow grade and 4 subjects with TIMI flow grade were added to better define the impact of antegrade flow through the IRA on myocardial salvage. A total of 121 subjects were included in this supplementary analysis. Eighty-nine subjects returned for a follow-up CMR (4 refused due to claustrophobia, 6 had a cardiac defibrillator placed after the first CMR study, 5 moved, and 17 were lost to follow-up). Clinical follow-up information for at least 6 months was available at the time of the second CMR study, or by phone interview plus chart review for 12 patients. Major adverse cardiac events (MACE) were defined as cardiac death, admission for heart failure, or need for heart transplantation. All patients gave written consent for their participation in the study, which was approved by the Northwestern University Institutional Review Board. Coronary angiography. Primary PCI was attempted in all patients. Symptom-to-balloon time was not available in 6 patients. All patients were pre-treated with aspirin (324 mg) and unfractionated heparin (5 U/kg). A total of 115 (95%) subjects were treated with glycoprotein IIb/IIIa inhibitors, which were given at the time of PCI. Multiple selective

3 JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 5, contrast injections were performed in the left main and right coronary arteries, and collateral flow was assessed before PCI. Two independent angiographers blinded to the CMR images reviewed all angiograms. The culprit lesion in the IRA was easily identifiable during PCI based on the angiographic findings of the lesion, clinical information, and the response to reperfusion, except in 1 case. The jeopardized myocardium distal to the culprit lesion in the IRA was evaluated using the modified BARI score as previously described (2). All distal arteries supplying the LV the distal left anterior descending, left circumflex, posterior descending, diagonal, marginal, and posterolateral arteries were graded depending on vessel length and caliber according to published criteria (4). Additionally, septal branches were arbitrarily assigned a maximum total score of 3 points. All units affected by the culprit lesion were summed and divided by the global score of the entire ventricle to estimate the myocardium at risk as a percentage of the LV myocardium. Antegrade flow in the infarct-related artery was characterized using the TIMI system. Angiographic collateral flow was assessed with a 4-grade scale using the Rentrop classification: grade indicating the absence of visually identifiable collateral vessels to grade 3 indicating complete retrograde filling of the IRA to the site of occlusion (5). CMR. CMR was performed in a 1.5-T Sonata or Avanto scanner (Siemens, Erlangen, Germany) at a mean of (range 1 to 7) days after admission and repeated in 89 subjects at 5 3 months. Images were ECG gated and obtained during repeated breath-holds using a body phasedarray receiver coil. A cine steady-state freeprecession sequence was used to assess LV function. Sequential 6-mm short-axis slices were prescribed every 1 mm to encompass the entire LV. Contrast-enhanced CMR images were acquired in identical positions starting 1 min after administration of.2 mmol/kg gadopentetate dimeglumine (Berlex, Montville, New Jersey) using a T1- weighted segmented inversion-recovery gradientecho TurboFLASH sequence (6). Typical voxel size was mm. Images were cropped, interpolated by a factor of 3 to facilitate border detection, deidentified, and randomized for further study. Using ImageJ software (National Institutes of Health, Bethesda, Maryland), an observer masked to the angiographic findings manually traced the borders of the epicardium and endocardium on short-axis cine images at end-diastole and end-systole to calculate LV myocardial volume and ejection fraction (EF). The areas of hyperenhancement on contrast-enhanced CMR images were planimetered as previously described (3). Infarct size, expressed as percentage of LV myocardial volume, was calculated as follows: (hyperenhanced myocardium volume/total LV myocardium volume) 1. Dark areas of absent contrast enhancement surrounded by hyperenhancement, considered as areas of microvascular obstruction, were included in the infarct size. An additional area of hyperenhancement in a remote zone not corresponding to the IRA and clearly isolated from the infarct zone was found in 8 studies, and these areas were retrospectively excluded from the reported infarct size. Myocardial salvage. Myocardial salvage was calculated by subtracting the CMR-derived infarct volume from the initial volume of jeopardized myocardium assessed by angiography. To correct for individual differences in LV mass, a myocardial salvage index (MSI) was calculated as the ratio between myocardial salvage and total LV wall volume as follows: MSI (myocardial salvage/total LV wall volume) 1, expressed as percentage of total LV wall volume. Segmental analysis. Segmental wall thickening was assessed by the consensus of 2 experienced observers blinded to the contrast-enhanced images using the recommended 17-segment model (7). All studies were randomly presented to the readers so that they were not aware of the study time, basal or followup. Wall thickening was visually scored as follows: normal, 1 mild or moderate hypokinesis, 2 severe hypokinesis, 3 akinesis, 4 dyskinesis. All segmental scores were summed to calculate the wall motion score (WMS) for each study. Similarly, the transmural extent of myocardial infarct for each segment was scored visually as (no infarction), 1 (1% to 25%), 2 (26% to 5%), 3 (51% to 75%), and 4 (76% to 1% of wall thickness). Additionally, the mean infarct transmurality score for every initial study was calculated by dividing the sum of hyperenhancement segmental scores by the number of segments with any delayed hyperenhancement. Statistical analysis. Quantitative data are reported as mean SD or number (percentage). Symptom onset-to-balloon time and door-to-balloon time are presented as median (25th percentile to 75th percentile). The agreement between BARI score and infarct size among 22 subjects with initial TIMI flow grade 1, collateral flow grade 1, and symptom-to-balloon time 4 h was studied by Pearson test and Bland-Altman analysis. Compar-

4 494 JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 5, 21 ison of means between groups with and without residual flow was performed by 1-way analysis of variance (ANOVA) with Bonferroni corrections or unpaired Student t test, except when these were not normally distributed. In this case, the Mann- Whitney U test or Kruskal-Wallis test was used when appropriate. Nonparametric stepwise multivariate linear regression analyses were conducted to identify independent predictors of MSI and infarct transmurality after rank transformation of these variables. A separate univariate ANOVA was conducted to test the interaction between time to reperfusion and the presence of residual flow to predict MSI and infarct transmurality. The population was divided in tertiles according to infarct transmurality extent as well as MSI to study segmental wall motion recovery from baseline to follow-up. For this purpose, comparisons between groups were performed using the withinsubjects and between-subjects effect ANOVA of repeated measures with Bonferroni correction. Finally, MACE occurrence was studied by Kaplan-Meier survival curves and log-rank tests for groups with infarct transmurality and MSI above or below the mean. The SPSS version 13 statistical package (SPSS Inc., Chicago, Illinois) was used, and a 2-tailed p value.5 was considered statistically significant. RESULTS Overall results. A total of 62 subjects had the culprit lesion located in the left anterior descending artery, 41 were in the right coronary artery, and 18 were in the left circumflex or ramus artery. The distribution of delayed hyperenhancement mapped according to the 17-segment model had been previously reported (8). Initial TIMI flow grade and collateral vessels. Table 1 depicts the clinical, angiographic, and CMR characteristics of the population according to the TIMI flow grade and collateral flow. When compared with an occluded artery (TIMI flow grade to 1, n 17), the presence of a patent IRA (TIMI flow grade 2 to 3, n 14) was associated with a smaller infarct size, greater MSI, and less mean infarct transmurality (p.1 for all). The presence of initial flow of TIMI flow grade 1 (n 14) was not associated with a benefit in MSI when compared with the TIMI flow grade group (n 93) ( vs , respectively, p.9). Table 1. Clinical, Angiographic, and CMR Characteristics of the Population According to the Presence of Antegrade or Collateral Flow Antegrade Flow Collateral Flow TIMIto1 (n 17) TIMI2to3 (n 14) p Value Poor Collateral Vessels (n 65) Good Collateral Vessels (n 42) p Value Age (yrs) Male 91 (85) 9 (64).6 54 (83) 37 (88).58 Maximal CPK-MB (mg/dl) Symptom-to-balloon time (min) 21 (135 36) 23 (112 29) (13 31) 218 (16 511).68 ACE inhibitor 87 (85) 8 (61).5 52 (84) 35 (87).77 Beta-blocker 96 (94) 14 (1) (92) 39 (97).39 Angiographic findings Anterior infarction 53 (49) 9 (64) (55) 17 (4).16 Multivessel disease 66 (62) 4 (29).5 35 (54) 31 (74).5 Final TIMI flow grade 3 94 (88) 13 (93).9 54 (83) 4 (95).29 BARI score (% LV wall) CMR findings LV end-diastolic index (ml/m 2 ) LV end-systolic index (ml/m 2 ) Ejection fraction (%) WMS Infarct size (% LV wall) Infarct transmurality score Myocardial salvage Myocardial salvage (% LV wall) MSI Values are presented as number (percentage) or mean SD. Symptom onset to balloon time is presented as median (25th percentile to 75th percentile). ACE angiotensin-converting enzyme; BARI Bypass Angioplasty Revascularization Investigation Myocardial Jeopardy Index; CMR cardiac magnetic resonance; CPK-MB creatinphosphokinase myocardial band; LV left ventricular; MSI myocardial salvage index; TIMI Thrombolysis In Myocardial Infarction; WMS wall motion score.

5 JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 5, Among subjects with initial TIMI flow grade to 1, those with good collateral vessels (grade 2, n 42) had better EF (p.5), had better summed WMS (p.1), and tended to have higher although not significant MSI (p.6) than those with poor collateral vessels (grade 1, n 65). Additionally, subjects with good collateral vessels had less infarct transmurality (p.1) (Table 1). Figure 1 depicts 4 examples of the effect of collateral flow in infarct transmurality. Time to reperfusion. The study population was divided into 4 subgroups according to the symptomto-balloon time: 2 h,2to3h,3to4h,and 4 h. Increasing symptom-to-balloon time was associated with a progressive reduction in MSI that was significant only among patients with poor residual flow those having TIMI flow grade to 1 and no collateral vessels (p.1 for the trend) (Fig. 2A). Reperfusion beyond 4 h conferred negligible MSI among subjects with poor residual flow as compared with patients with good residual flow either TIMI flow grade 2 to 3 or good collateral vessels (.2 1. vs , p.1). Similarly, increasing symptom-to-balloon time was associated with a significant increase in infarct transmurality only in the absence of residual flow (p.1 for the trend) (Fig. 2B). Univariate linear regression analysis identified a significant interaction between symptom-to-balloon time and the presence of residual flow for MSI as the dependent variable (F statistic 3.57, p.5) but not for infarct transmurality (F 1.16, p.3). Major differences in MSI between subjects with good versus poor residual flow occurred mainly beyond 3 h of symptom-to-balloon time, despite no differences in the initial myocardium at risk (Table 2). Twenty-two subjects had an initial TIMI flow grade 1, collateral grade 1, and symptom-to- Figure 1. Angiograms and Representative Short- and Long-Axis Contrast-Enhanced CMR Images in Patients With Good and Poor Collateral Vessels The first 2 rows correspond to 2 patients with anterior infarction with similar jeopardy scores (32% of the left ventricle) and time to reperfusion (144 and 2 min). The images in the last 2 rows were obtained in 2 patients with inferior infarction with similar jeopardy scores (22% and 17% of the left ventricle, respectively) reperfused after 21 min of symptom onset. The red arrows depict the site of coronary occlusion on the angiograms. The white arrows on the CMR indicate the presence of a rim of viable epicardial myocardium (dark) surrounding a thin subendocardial infarct (white) in patients 1 and 3 who had good collateral flow (grade 2) as indicated by the green arrows, as compared with complete transmural infarction in patients 2 and 4 with poor collateral flow (grade ). CMR cardiac magnetic resonance.

6 496 JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 5, 21 A Mean Myocardial Salvage Index (MSI) <2 hs (n=2) to 3 hs (n=28) to 4 hs (n=24) Symptom-to-Balloon P=NS >4 hs (n=43) B Mean Infarct Transmurality Score <2 hs (n=2) 1.82 * to 3 hs (n=28) to 4 hs (n=24) Symptom-to-Balloon P=NS >4 hs (n=43) Good residual flow Poor residual flow Figure 2. Impact of Time to Reperfusion on Myocardial Salvage and Infarct Transmurality According to the Presence or Absence of Residual Flow Increasing symptom-to-balloon time was associated with a decrease in MSI (A) and an increase in mean infarct transmurality score (B), particularly for subjects with poor residual flow (pink bars) as opposed to subjects with good residual flow (green bars); p.1 for both trends. p.5 for direct comparison between the subgroups with and without residual flow. p.1 for direct comparison between the subgroups with and without residual flow. MSI myocardial salvage index. balloon time 4 h. The BARI score correlated highly with the infarct size by CMR (Pearson R.88, p.1). Bland-Altman analysis in this group showed a mean bias between jeopardy score and infarct size of.32% of LV wall volume (95% confidence interval from 1.7% to 2.35%). The Table 2. Impact of Residual Flow According to Symptom-to-Balloon Time Among 115 Patients With Known Symptom-to-Balloon Time Symptom-to-Balloon Time Good Residual Flow Poor Residual Flow p Value 2 h(n 2) Area at risk (% LV wall) Infarct size (% LV wall) MSI (% LV wall) Infarct transmurality to3h(n 28) Area at risk (% LV wall) Infarct size (% LV wall) MSI (% LV wall) Infarct transmurality to4h(n 24) Area at risk (% LV wall) Infarct size (% LV wall) MSI (% LV wall) Infarct transmurality h(n 43) Area at risk (% LV wall) Infarct size (% LV wall) MSI (% LV wall) Infarct transmurality Abbreviations as in Table 1. 95% agreement between the 2 techniques was 1.75% to 11.39% of LV wall volume. This group of 22 patients also had greater infarct transmurality as compared with the remainder of the study group (3..5 vs , p.1). By multivariate linear regression analysis, the angiographic area at risk, a patent artery (TIMI flow grade 2), symptom-to-balloon time, the presence of microvascular obstruction, and collateral flow grade 2 were found to be independent predictors of myocardial salvage. Likewise, TIMI flow grade 2, symptom-to-balloon time, collateral flow grade 2, and microvascular obstruction were independent predictors of infarct transmurality (Table 3). MSI, infarct transmurality, wall motion recovery, and MACE. The MSI correlated inversely with WMS at baseline (R.27, p.1) and at follow-up Table 3. Multivariate Predictors of Myocardial Salvage and Infarct Transmurality Dependent Variable Independent Variables MSI Infarct Transmurality Symptom-to-balloon time p.1 p.1 (quartiles) Microvascular obstruction p.1 p.27 Initial TIMI flow p.1 p.1 Collateral flow grade p.15 p.1 Area at risk (BARI score) p.1 p.95 Abbreviations as in Table 1.

7 JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 5, (R.38, p.1). Infarct transmurality also correlated with WMS at baseline (R.52, p.1) and at follow-up (R.58, p.1). The MSI and infarct transmurality were inversely correlated at baseline (R.56, p.1). When the entire cohort was divided into tertiles based on the MSI ( 3.6%, 3.6% to 1.9%, and 1.9%), a higher MSI was associated with a better WMS at baseline and follow-up. By ANOVA of repeatedmeasures analysis, the increase of MSI predicted a better recovery of segmental wall function at follow-up (Fig. 3). Accordingly, the same associations and changes in WMS were observed when the study group was divided into tertiles according to infarct transmurality ( 2, 2 to 3, and 3) (Fig. 4). After a mean follow-up of days, there were no deaths, 1 heart transplant, and 13 patients readmitted for heart failure. Among 6 patients with cardiac defibrillators, no appropriate defibrillator discharges were observed. These events occurred in 12 patients with MSI below the mean (9.31% LV wall), and in 2 cases with MSI above the mean (log rank chi-square 5.4, p.5). DISCUSSION A Mean WMS B Change in Mean WMS <3.6 (n=28) to 1.9 (n=32) MSI (% LV Wall Volume) at Baseline P< >1.9 (n=27) Figure 3. Impact of MSI on the Recovery of Segmental Wall Motion Subjects were divided into tertiles based on the MSI. The mean WMS improved significantly from the baseline (yellow bars) to the follow-up (green bars) studies in all subgroups (A). A greater absolute change in WMS (B) occurred in subjects with greater MSI. p.1 by analysis of variance of repeated measures between baseline and follow-up values. MSI myocardial salvage index; WMS wall motion score. We previously showed that prompt reperfusion and angiographic collateral vessels may impact myocardial salvage and infarct transmural extent among patients with an occluded IRA. In the current investigation, we found that in addition to time to reperfusion and collateral vessels, the angiographic area at risk and the initial TIMI flow grade at the time of PCI are independent predictors of myocardial salvage by multivariate analysis. The novel index of myocardial salvage described here compares favorably with infarct transmurality to predict wall motion recovery after an acute STEMI. Previous experimental studies have shown that the final infarct size closely correlates with the mass of jeopardized myocardium within the territory of the IRA (9). It is known that reperfusion of an occluded artery results in greater improvement in regional LV function when collateral vessels are present in the acute phase of myocardial infarction (1). However, the adjunctive effect that collateral flow might have to increase myocardial salvage is controversial. Some contemporary clinical studies using nuclear perfusion imaging showed no differences in infarct size among patients with or without collateral flow (11), as opposed to other previous experimental and clinical studies (1,9,12). An angiographic technique, however, can anatomically determine the area at risk independently of perfusion. We have shown clinically an association between time to reperfusion, collateral flow, and pre-reperfusion coronary flow on maintaining epicardial myocardial viability. In a prior publication from our group that included 74% of the current population, we had already reported a reduction in infarct transmural extent among patients with welldeveloped collateral vessels or prompt reperfusion at the time of primary PCI (2). In the multivariate analysis of the current study, we have identified that the contribution of the initial TIMI flow grade 1 to myocardial salvage is greater than that provided by collateral vessels or time to reperfusion. In our previous report, we proposed the use of the infarct endocardial surface area as a measure of area at risk because this parameter was not influenced by collateral flow or reperfusion beyond the first hour of

8 498 JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 5, 21 A Mean WMS B Change in Mean WMS >3 (n=24) to 3 (n=36) Mean Infarct Transmurality at Baseline < 2 (n=27) Figure 4. Impact of Infarct Transmurality Score on the Recovery of Segmental Wall Motion Subjects were divided into tertiles based on the mean infarct transmurality score. The mean WMS improved significantly from the baseline (yellow bars) to the follow-up (green bars) studies (A). A greater absolute change in WMS (B) occurred in subjects with less infarct transmurality. p.1 by analysis of variance of repeated measures between baseline and followup values. WMS wall motion score. symptoms. In the current study, we found that the infarct endocardial surface area was consistently smaller than the angiographic area at risk among subjects with a patent IRA (TIMI flow grade 2 to 3, data not presented). It might be speculated that in addition to infarct transmural extent reduction, antegrade residual flow may also limit the lateral boundaries of the infarct as opposed to collateral flow. The pivotal studies by Reimer and Jennings (9) emphasized the relatively narrow time window for salvage after reperfusion in a dog model. Several recent studies documented that reperfusion must be established within the first 3 h of onset of symptoms to achieve significant myocardial salvage (13). Likewise, we observed a rapid decay in myocardial salvage during the first few hours of symptoms and confirmed that an increase in time to reperfusion is associated with an increase in infarct transmurality (14). However, there exists an important yet unrecognized interplay between the time to reperfusion and the presence of residual coronary flow within the area at risk. Myocardial salvage within the first 4 h of symptoms was greatest among patients with intact residual flow. Beyond 4 h of symptoms, significant salvage only occurred in the presence of well-developed collateral vessels or preserved antegrade flow through the infarct-related lesion. Our data support the hypothesis that residual flow within the area at risk increases the time window for revascularization in humans and plays an important role in limiting infarct progression and subsequent recovery of regional wall motion. Therefore, strategies that promote patency of the IRA and favor collateralization result in maximizing myocardial salvage and better prognosis. Myocardial ischemia causes cellular swelling and interstitial edema through an increase in plasma membrane permeability and an increase in cellular and extracellular osmolarity. These changes can be depicted as areas with elevated signal intensity on T2-weighted CMR imaging. It has been shown that the area at risk as determined by T2-weighted CMR is greater than the infarct zone depicted by contrast-enhanced viability imaging in both reperfused (15) and nonreperfused animal models (16), allowing quantification of myocardial salvage. Recently, Carlsson et al. (17) prospectively validated this method against nuclear perfusion techniques in a population with occluded IRA. They found an excellent agreement between the areas at risk depicted by single-photon-emission computed tomography and T2-weighted imaging performed 1 week after infarction. A good correlation in measuring area at risk between the BARI score and T2-weighted imaging has also been reported (18). Taking into account these validation studies and growing evidence showing its value to quantify myocardial salvage in a single study, it is possible that T2-weighted imaging will become the preferred method for assessing myocardial salvage after STEMI. However, the T2-weighted technique also has major limitations, including limited signal-tonoise ratio, imaging artifacts, adjacent signal from ventricular blood pool, and the need of performing the study within 1 week of the event. In addition, it remains to be clarified whether estimates of area at risk using local edema account for differences in residual flow provided by collateral vessels or antegrade flow in the IRA territory. In this regard, the combined an-

9 JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 5, giographic and CMR approach may represent an alternative to T2-weighted CMR imaging, especially in the evaluation of retrospective studies. Study limitations. This methodology may not be appropriate to estimate MSI in cases of non STEMI, in which the high incidence of multiple severe lesions with normal antegrade flow could impede accurate identification of the culprit artery. This BARI score anatomical approach also cannot distinguish between the benefit provided by residual or collateral flow and that provided by reperfusion. Our ability to detect real differences in total collateral flow, especially in the group with collateral flow grade 1, might have been improved with the use of pressure-derived collateral flow, but these methods are not easily incorporated into routine clinical practice. In any case, appropriate correction for angiographic collateral grade may be applied when comparing the efficacy of reperfusion therapies. Additionally, the CMR studies were not performed on the day of infarction, which might have introduced a higher variability in infarct size measurement. Finally, we included a small sample of highly selected patients with few events, which confines any definitive conclusion regarding the clinical usefulness of this novel index to predict clinical outcomes. Our findings should be confirmed in larger studies. CONCLUSIONS Rapid restoration and maintenance of residual coronary flow results in greater myocardial salvage and reduction in infarct transmurality, both of which impact recovery of regional LV function. Utilizing a combination of an anatomical measurement of the area at risk with infarct size derived by CMR allows an independent assessment of myocardial salvage. This combined angiographic CMR strategy could be useful when comparing the efficacy of different reperfusion therapies or strategies, allowing sample size reduction and overcoming the logistical and technical limitations of previous approaches for estimating myocardial salvage. Importantly, the time-related transmural progression of infarction is greater in patients with no residual flow in the jeopardized myocardium, making collateral and antegrade flow in the IRA a potential important target for new therapies. Acknowledgments The authors thank Schnabel Samson, RN, for her efforts in patient recruitment and project coordination, and Raffy Syegco, RN, for his contribution in data collection. Reprint requests and correspondence: Dr. Edwin Wu, Department of Medicine, Cardiology Division, Feinberg School of Medicine, 676 North St. Clair Street, Suite 6, Chicago, Illinois ed-wu@ northwestern.edu. REFERENCES 1. Maruoka Y, Tomoike H, Kawachi Y, Noguchi K, Nakamura M. 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