Clinical Implications of the ‘No Reflow’ Phenomenon
A Predictor of Complications and Left Ventricular Remodeling in Reperfused Anterior Wall Myocardial Infarction
Background Recent studies demonstrated that the “no reflow” phenomenon after coronary reflow implies the presence of advanced myocardial damage. In this study, we verified the prognostic value of the detection of this phenomenon by studying complications, left ventricular morphology, and in-hospital survival after acute myocardial infarction (AMI).
Methods and Results The study population consisted of 126 patients with a first anterior AMI. All patients received coronary reflow within 24 hours of onset of symptoms and underwent myocardial contrast echocardiography (MCE) before and shortly after coronary reflow with an intracoronary injection of sonicated microbubbles. From contrast reperfusion patterns, patients were divided into two subsets: those with MCE no reflow (47 patients, 37%) and those with MCE reflow (79 patients). There was no difference in the frequency of arrhythmia or coronary events between the two subsets. Pericardial effusion and early congestive heart failure were observed more frequently in patients with MCE no reflow than in those with MCE reflow (26% versus 4%, P<.05; 45% versus 15%, P<.05, respectively). Congestive heart failure tended to be prolonged in those with MCE no reflow, and 3 patients (7%) of this subset died of pump failure. Left ventricular end-diastolic volume progressively increased in the convalescent stage in patients with MCE no reflow (early versus late, 145±43 versus 169±60 mL, P<.001), whereas it decreased in those with MCE reflow (154±42 versus 144±44 mL, P<.01).
Conclusions The substantial size of the MCE no reflow phenomenon at coronary reflow conveys useful information about an outcome of coronary intervention and left ventricular remodeling in individual patients with anterior wall AMI, although these are suggestive results in a limited number of patients.
In acute myocardial infarction (AMI), several variables have been proposed to identify the patients at high risk for death. They include advanced age, extent of ECG changes, evidence of acute failure of the left side of the heart, a history of previous infarction or concomitant diabetes mellitus, and patency of the infarct-related artery.1 2 In early clinical decision making, it would be much more valuable if we could identify individuals with a relatively good or an exceptionally unfavorable prognosis among the high-risk group. Several studies imply that coronary reperfusion generally improves left ventricular performance and patient prognoses; however, coronary reperfusion does not necessarily provide preserved left ventricular performance and good patient prognoses, and predicting high-risk patients among reperfused patients remains difficult.2 3 4 5
Although it is generally believed that the patent epicardial coronary vessel should guarantee flow at the microvascular beds in AMI, ischemic episodes may often break down the coronary microvasculature; thus, flow to the infarct myocardium may be markedly reduced despite the angiographic documentation of reflow in the infarct-related artery (the “no reflow” phenomenon).6 7 8 9 10 11 12 In our previous studies using myocardial contrast echocardiography (MCE), the recovery in myocardial contractile function was significantly worse in patients with substantial MCE no reflow than in those with MCE reflow.13 14 However, clinical outcomes of patients with and without no reflow are still unknown. Although a large myocardial infarction triggers left ventricular remodeling, which worsens patient morbidity and mortality,15 16 it is currently difficult to predict ventricular dilation in individual reperfused patients. Left ventricular remodeling or dilation may be predicted on the basis of the presence or absence of MCE no reflow in the early phase.
This study was attempted to verify the prognostic value of detecting MCE no reflow. Specifically, in-hospital survival, complications, and left ventricular morphology were related to the MCE reflow patterns in 126 consecutive patients with reperfused anterior wall AMI.
MCE was performed in 140 consecutive patients who were admitted to the Coronary Care Unit of the Sakurabashi Watanabe Hospital for the first MI of the anterior wall from February 1989 through July 1994. The diagnosis of AMI 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 a threefold increase in serum creatine kinase activities. Fourteen patients were excluded from analysis because of inadequate image quality (8 patients), multivessel disease (4 patients), or inadequate coronary reperfusion even after interventions (Thrombolysis in Myocardial Infarction Trial [TIMI] grade 0, 1, or 2 flow; 2 patients). Therefore, this report is based on the remaining 126 patients (96 men, 30 women; mean age, 55 years [range, 38 to 75 years]). Eight patients demonstrated a patent coronary artery (TIMI grade 3 flow) at the initial coronary angiography performed within 24 hours after the onset of symptoms, and the intervention was not performed. The other 118 patients underwent intracoronary thrombolysis (tissue plasminogen activator 1 200 000 U or urokinase 480 000 to 960 000 U; 19 patients) or coronary angioplasty (99 patients) to the culprit lesion and achieved successful coronary reflow within 24 hours after the onset of chest pain. Informed consent was obtained from each patient by an investigator. The study protocol was approved by the hospital’s Ethics Committee.
In the early stage, catheterization was performed by use of the femoral approach after the injection of 100 U/kg heparin. Each patient rested in the supine position. On completion of the diagnostic coronary arteriography and left ventriculography, 2 mL sonicated ioxaglate (Hexabrix-360, Tanabe) containing microbubbles (mean size, 12 μm) was injected into the left coronary artery for MCE as previously described.13 14 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 the contrast injection and was continued for an average of 30 seconds with a 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 injected into the right coronary artery. MCE was repeated about 16 minutes (range, 10 to 24 minutes) after successful reflow was confirmed with coronary arteriography. A II-lead ECG was continuously monitored during and after MCE.
After coronary reflow, heparin was continued for 48 hours and was adjusted to maintain the activated clotting time to >180 seconds. All patients were maintained on a regimen of aspirin or ticulopidine and cumadine. If required, oral nitrates, calcium antagonists, β-blockers, diuretics, and/or angiotensin-converting enzyme inhibitors were added and continued until the late-stage examination.
A lead V5–equivalent ECG was monitored continuously until a mean of 7 days after the infarction (range, 3 to 10 days) for the detection of arrhythmias. Two-dimensional echocardiography was performed before coronary reflow and at days 2, 3, 7, 14, and 28 of the infarction with a commercially available electrical sector scanner (model SSH-65A or SSH-260A, Toshiba; carrier frequency, 3.75 MHz). In each echocardiographic examination, parasternal long-axis and short-axis views at the levels of the mitral valve and midpapillary muscle and an apical long-axis view were recorded on 1.25-cm videotape with the same VHS recorder. The presence or absence of pericardial effusion was also evaluated.
Coronary arteriography, left ventriculography, and MCE were repeated at a mean of 25 days after the infarction (range, 24 to 29 days) by use of the right brachial approach. All medications were withdrawn at least 12 hours before cardiac catheterization.
Analysis of MCE Data
Echocardiographic images were analyzed with a commercially available off-line computer system (model LA-500, PIAS or Color Cardiology Workstation, TomTec Imaging). End-diastolic echocardiographic frames after contrast injection were selected with synchronization to the peak of the R wave on the ECG. An operator selected the echocardiographic images with the best delineation between contrast-enhanced and nonenhanced myocardium to determine risk area,17 18 which was determined to be an area showing no contrast enhancement in the prereflow MCE from injection into either the right or left coronary artery. In cases of TIMI grade 3 flow at the initial coronary angiography, the extent of abnormal contraction segment of the left ventricle was considered the risk area.18 MCE performed just after coronary reflow was analyzed in the same fashion, and when the endocardial length of the area showing residual contrast defect exceeded a fourth of that of the risk area, myocardial reperfusion in the corresponding segment was considered incomplete (MCE no reflow). Areas showing contrast defects were always successfully defined, and measurements of the size of the residual contrast defects were highly reproducible, as mentioned previously.13
Analysis of Catheterization Data
The right anterior oblique views of left ventriculograms in baseline and the late stage were analyzed to measure left ventricular end-diastolic volume and global left ventricular ejection fraction with the area-length method. The regional wall motion of the infarct zone was evaluated quantitatively and expressed as SD per chord with the centerline method.19 The percent diameter stenosis of the infarct-related artery also was determined after reflow and at follow-up. Collateral channels were graded in the initial coronary arteriograms as follows: 0=no collaterals, 1=incomplete slow opacification in the distal vessel, 2=slow but complete opacification of the distal vessel, and 3=distal vessel opacified as well as the normal vessel. An angiographer blinded to patient data analyzed the cinefilms in a random sequence.
In-Hospital Data Collection
The patients were followed up for the occurrence of complications until hospital discharge. Data on clinically relevant in-hospital events (death from any cause and reinfarction) were carefully collected in the study forms. Another investigator also reviewed data on these patients. The type and frequency of ventricular arrhythmia were evaluated by Holter monitoring on the day of the infarction, and ECG monitors recorded continuously until at least 5 days after the infarction. Malignant arrhythmia was defined as ventricular tachycardia (a minimum of three consecutive beats of ventricular origin at a rate of >100 beats per minute) and ventricular fibrillation observed at any time during hospitalization. Left ventricular heart failure was defined as the presence of clinical congestive heart failure (the presence of a third heart sound, Killip class ≥2, Forrester subset of 2 or 4, dyspnea, or evidence of pulmonary congestion on chest radiographs). Early postinfarction angina was defined as angina pectoris observed within 7 days after the onset of infarction. Symptom-limited bicycle ergometer exercise test was performed at a mean of 24 days after the infarction (range, 22 to 26 days) to evaluate the presence of post-AMI ischemia (late postinfarction angina). Pericardial effusion and cardiac tamponade were diagnosed on the basis of clinical and echocardiographic findings. Restenosis was defined as a loss of initial gain by 50% in cases of coronary angioplasty and as an increase in the American Heart Association classification of coronary stenosis of more than one grade in cases of intracoronary thrombolysis.
All data are expressed as mean±SD. Univariate analyses of differences between reflow and no reflow groups were performed with one-way ANOVA (Scheffé’s F test) for continuous outcome variables and by χ2 tests for discrete outcome variables. If a small number (less than five) was included, Fisher’s exact test was applied instead of χ2 tests for the analysis of discrete variables. Statistical analysis of temporal changes in certain variables was computed by ANOVA and Scheffé’s F test for repeated measures. The contribution of factors to early and late congestive heart failure and left ventricular dilation was evaluated by multivariate regression analysis as explained later. Differences were considered significant at P<.05.
The risk area was well opacified in 79 patients as indicated by MCE performed shortly after coronary reflow (MCE reflow), whereas 47 patients (37%) demonstrated a substantial size of the residual contrast defects within the risk area (MCE no reflow). Table 1⇓ summarizes patient characteristics of these two subsets. There were no differences in age, sex, culprit lesion, time from the onset of symptoms to reperfusion, angiographic collateral grade, and frequency of coronary risk factors between the two subsets. All patients with MCE no reflow subsequently developed Q waves in 12-lead surface ECG, but 27 of 79 patients with MCE reflow (34%) manifested non–Q-wave myocardial infarction. There were no significant differences in the in-hospital medications between the two subsets.
Complications and In-Hospital Prognosis
Table 2⇓ summarizes coronary events and findings. There were no differences in the frequency of restenosis, reocclusion, early and late postinfarction angina, or recurrent ischemia (extension and recurrent infarction) between the two subsets. Table 3⇓ summarizes in-hospital complications and survival of the two subsets. Frequencies of malignant arrhythmias shortly after coronary reflow and the total number of malignant arrhythmia, excluding reperfusion arrhythmia, were significantly higher in patients with MCE no reflow than those with MCE reflow. Pericardial effusion was observed more frequently in patients with MCE no reflow than in those with MCE reflow. Cardiac tamponade was not observed in patients with MCE reflow but was observed in 6% of patients with MCE no reflow. Congestive heart failure within 3 days of the AMI was observed more frequently in the patients with MCE no reflow than those with MCE reflow. Congestive heart failure, if it occurred, tended to last beyond the third day in patients with MCE no reflow, whereas remission of heart failure was observed within 3 days in most patients with MCE reflow. There were, however, no differences in hemodynamic variables and in-hospital medications between the two subsets 1 month later (reflow versus no reflow: pulmonary capillary wedge pressure, 9±5 versus 10±6 mm Hg; cardiac index, 3.3±0.6 versus 3.2±0.9 L·min−1·m−2).
One patient with MCE reflow died in the hospital; the cause of death was a blowout-type cardiac rupture that occurred 2 hours after the reperfusion. In contrast, three patients (6%) with MCE no reflow died of congestive heart failure 12, 17, and 57 days after the AMI.
Left Ventricular Function and Morphology
Adequate left ventriculograms were obtained in both the early and late stages in 116 patients: 76 with MCE reflow and 40 with MCE no reflow. Reasons for incomplete examinations were arrhythmia or incomplete opacification during left ventriculography (5 patients), in-hospital death (3 patients), and no left ventriculography in the early stage (2 patients). Baseline regional contractile function was better in patients with MCE reflow. A significant improvement in left ventricular global function was observed in patients with MCE reflow, but there was a little improvement in patients with MCE no reflow (MCE reflow, 46±11% versus 57±13% [early versus late], P<.001; MCE no reflow, 38±11% versus 43±12%, P<.05). Similarly, the regional contractile function in the infarct zone was well preserved in the early stage and showed more improvement in patients with MCE reflow compared with those with MCE no reflow (MCE reflow, −3.0±0.6 versus −2.1±1.0 SD per chord [early versus late], P<.001; MCE no reflow, −3.4±0.4 versus −3.0±0.7 SD per chord, P<.01). Therefore, the patients with MCE reflow manifest much better (P<.001) regional function than those with MCE no reflow in both the early and late stages.
There were no differences in left ventricular end-diastolic and systolic volumes in a baseline study between the two subsets (see the Figure⇓). In patients with MCE reflow, left ventricular end-diastolic volume decreased significantly from baseline to the late stage (154±42 versus 144±44 mL, P<.01). In patients with MCE no reflow, however, left ventricular end-diastolic volumes increased significantly from baseline to the late stage (145±43 versus 169±60 mL, P<.001), implying left ventricular remodeling. Thus, end-diastolic volume was greater in patients with MCE no reflow than those with MCE reflow in the late stage. In addition, substantial left ventricular dilation (an increase in end-diastolic volume by >20%) was observed in 17 of 40 patients with MCE no reflow and 6 of 76 patients with MCE reflow. Therefore, sensitivity, specificity, and positive predictive value of MCE no reflow for future substantial left ventricular dilation are 43%, 92%, and 74%, respectively.
Factors Contributing to Heart Failure and Left Ventricular Dilation
To evaluate the contribution of each factor to early and late congestive heart failure and left ventricular dilation (an increase in left ventricular end-diastolic volume by >20%), multiple logistic regression analysis was performed. The variables shown in Table 4⇓ were used for the analysis. For multiple regression analysis, factors showing a value P<.1 in univariate analysis were selected. Multiple regression analysis depicted MCE no reflow, preseptal occlusion (possibly related to the size of the risk area), and age as significant variables to determine early congestive heart failure. On the other hand, only MCE no reflow contributed significantly to late congestive heart failure. Similarly, MCE no reflow is only one factor that is a significant variable for determining significant left ventricular dilation. Therefore, MCE no reflow contributed significantly to these clinical observations. Together, however, these variables could explain <30% of the total effects of these clinical observations.
The epicardial coronary vessel, even if patent, may not necessarily guarantee flow at the microvascular beds in patients with AMI because ischemic episodes may often break down the coronary microvasculature.10 12 14 15 20 21 A substantial no reflow area was observed shortly after successful coronary angiographic reflow in 37% of the patients with acute anterior AMI in this study. MCE no reflow not only resulted in poor functional recovery but also was associated more frequently with pericardial effusion, cardiac tamponade, and congestive heart failure that tended to last beyond 4 days compared with MCE reflow. In addition, the left ventricular cavity was dilated in the late stage despite the patent infarct-related artery in patients with MCE no reflow, whereas ventricular volumes decreased in the convalescent stage in patients with MCE reflow. Thus, our results documented that the MCE no reflow phenomenon strongly discriminates individual patients with poor outcomes and left ventricular remodeling from those with favorable outcomes.
No Reflow Phenomenon and Complications
It is important in the decision of therapeutic strategy to predict the severity and duration of left ventricular dysfunction in the early stage of an AMI. In our patients with MCE no reflow, clinical congestive heart failure was observed frequently on the day of AMI and tended to last 4 days or longer, whereas heart failure, if present, showed remission within 3 days of the AMI in most patients with MCE reflow. The reason for the higher frequency of early congestive heart failure in patients with MCE no reflow is still not clear. Left ventricular contractile function before coronary reflow was better in patients with MCE reflow than those with MCE no reflow; this may at least partially account for the difference in the frequency of early congestive heart failure. Multiple regression analysis indicated that the no reflow phenomenon, the culprit lesion reflecting the size of the risk area, and age are related to early congestive heart failure. Congestive heart failure was observed frequently beyond 4 days after reperfusion in patients with MCE no reflow. Multiple regression analysis revealed that MCE no reflow is the only factor contributing to late congestive heart failure. AMI was larger in patients with MCE no reflow than in those with MCE reflow; thus, it may take longer for the left ventricle to adapt to a larger infarction. The differences in the frequency and duration of congestive heart failure between the subsets may be explained this way. The hemodynamic derangement was no longer observed at the follow-up study (hemodynamic data), possibly because the left ventricle successfully adapted in the late stage in any patient with congestive heart failure at that time.
Pericardial effusion and cardiac tamponade were observed frequently in patients with MCE no reflow. In any patient with cardiac tamponade, we successfully performed pericardial drainage, and bloody effusion was drained. Therefore, cardiac tamponade may be attributed to hemorrhagic infarction caused by coronary reperfusion, oozing rupture, or both. In contrast, all patients with pericardial effusion manifested clinical signs of pericarditis (friction rub or chest pain augmented by respiration and curable with antiinflammatory drugs). Although pericardial drainage was not performed, postinfarction pericarditis was a probable diagnosis. The transmurality of MI should contribute to the occurrence of pericarditis because Q-wave MI subsequently developed in all patients with MCE no reflow, whereas 34% of patients with MCE reflow manifested non–Q-wave infarction. It is well known that pericarditis is observed more frequently in cases of Q-wave than non–Q-wave MI. Transmural myocardial damage with intramural hemorrhage may lead to cardiac tamponade; however, no pathological data were obtainable in our patients to support our speculation.
We initially anticipated that coronary events (recurrent ischemia, early and late postinfarction angina, restenosis, and reocclusion) may be more frequent in patients with MCE no reflow than in those with MCE reflow because microvascular damage is likely to slow the epicardial coronary blood flow and because the stagnation of blood flow may accelerate local thrombus formation. However, there was no difference in the frequency of any coronary event between patients with and without MCE no reflow. Therefore, coronary microvascular damages may not necessarily increase the frequency of coronary events or augment the rate of coronary restenosis. These observations may be related to the following: coronary angioplasty performed in most of our patients with the residual coronary stenosis of <50% or adequate heparinization in the early stage, followed by adequate cumadination and antiplatelet therapy until the follow-up study.
Four patients experienced cardiac death. Three patients (6%) with MCE no reflow died of congestive heart failure. In these patients, substantial no reflow was observed despite the successfully recanalized coronary artery. Congestive heart failure lasted beyond 4 days and was resistant to intra-aortic counterpulsation, diuretics, catecholamine, or load reduction therapy. Thus, if the no reflow phenomenon is documented in the large areas of the left ventricle, we should prepare ourselves for intractable and prolonged congestive heart failure. In contrast, a patient with MCE reflow died of a blowout-type cardiac rupture observed 2 hours after successful coronary reflow. Although the study population is limited, cardiac rupture may not be predictable on the basis of postreflow MCE patterns.
Left Ventricular Remodeling
The progressive left ventricular dilation is observed sometimes during the early convalescent period of AMI.16 22 Although this dilation appears to represent a compensatory mechanism for suppressed ventricular function, it may profoundly derange left ventricular function and affect patient prognoses.23 Although coronary reperfusion per se might have a beneficial effect of preventing left ventricular dilation,16 22 24 a substantial population (19% to 42%) of patients still manifests significant left ventricular dilation, and predicting left ventricular dilation in reperfused patients is still difficult. Among factors that influence ventricular dilation, the resultant size of the infarction or asynergy is considered to be a major determinant of left ventricular dilation in reperfused patients.15 16 Therefore, if we could estimate the size of the MI, we could predict the left ventricular dilation in the early stage of the infarction.
The results of our previous and present studies showed that MI as assessed with left ventricular ejection fraction, regional wall motion, and the extent of asynergy is significantly larger in patients with MCE no reflow than those with MCE reflow. Patients with MCE no reflow manifested significant left ventricular dilation from the early to late stage. In contrast, end-diastolic volume decreased in the late stage in patients with MCE reflow. These findings are compatible with our previous observations. Therefore, MCE no reflow seems to be a predictor of left ventricular dilation in patients with reperfused anterior wall MI.
The results of this study should be considered in light of several limitations. First, our method depends heavily on echocardiographic image quality. Second, contrast intensity is influenced by many factors, including the size and number of microbubbles; 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. The timing of MCE after coronary reflow is another factor affecting the size of the no reflow phenomenon.12 Third, only patients with first anterior wall MI were enrolled in this study. Therefore, the prognostic value of MCE no reflow has not been established in patients with inferior or posterior wall MI or recurrent MI. Finally, our analysis was based on a comparison of in-hospital complications and angiographic data only; survival and quality of life in a longer follow-up period were not taken into consideration.
Assessment of microvascular perfusion seems to be essential in gaining further understanding of patient outcome and of the relation between intervention and outcome. Neither the patency status nor the severity of stenosis of the infarct-related artery indicates the extent of microvascular integrity, and MCE may be the only method currently available for assessment of the microvascular integrity. Thus, we may use MCE to identify patients with good or poor prognoses after AMI in a catheterization laboratory at the time of diagnostic angiography. The prompt assessment of both coronary anatomy and the quality of microvascular perfusion (and hence myocardial viability) may aid in decision making in individual patients. At present, however, the demonstration of no reflow may have little clinical usefulness in the management of these patients.
MCE assessment of reperfusion patterns provides a useful predictor of left ventricular remodeling in individual patients. If substantial no reflow is observed after coronary reflow, an advanced form of load reduction therapy is recommended to attenuate left ventricular dilation.25
MCE is inexpensive and can be performed in a catheterization laboratory in only a few minutes. However, obvious practical problems currently are connected with acquisitions of MCE in acute patients. Newly developed contrast media such as sonicated albumin solution can produce contrast enhancement of the left chambers and the myocardium through the contrast injection into the right or left atrium11 26 or the peripheral veins in canine experiments. Such new contrast media should expand the clinical application of MCE in the near future. With the advent of such contrast media, MCE can be performed to serially assess myocardial flow and viability after coronary reflow at bedside in the Intensive or Coronary Care Unit.
We greatly acknowledge the excellent technical assistance of Yuzo Sakagami, Yoshiki Jonishi, and Masakazu Ueda, the excellent secretarial assistance of Rie Nishizawa, and the statistical advice of Dr Kusuoka (Osaka University).
- Received January 23, 1995.
- Revision received July 26, 1995.
- Accepted August 25, 1995.
- Copyright © 1996 by American Heart Association
Braunwald E. Myocardial infarction, limitation of infarct size, reduction of left ventricular dysfunction and improved survival: should the paradigm be expanded? Circulation. 1989;79:441-444.
Kloner RA, Ganote CE, Jennings RB. The ‘no reflow’ phenomenon after temporary coronary occlusion in the dog. J Clin Invest. 1974;54:1496-1508.
Kloner RA, Rude RE, Carlson N, Maroko PR, DeBoer LWV, Braunwald E. Ultrastructural evidence of microvasular damage and myocardial cell injury after coronary artery occlusion: which comes first? Circulation. 1980;62:945-952.
Kloner RA, Ellis SG, Lange R, Braunwald E. Studies of experimental coronary artery reperfusion: effects on infarct size, myocardial function, biochemistry, ultrastructure, and microvascular change. Circulation. 1983;68(suppl I):I-8-I-15.
Johnson WB, Malone SA, Pantely GA, Anselone CG, Bristow JD. No reflow and extent of infarction during maximal vasodilation in the porcine heart. Circulation. 1988;78:462-472.
Kemper AJ, Force T, Kloner R. Contrast echocardiographic estimation of regional myocardial blood flow after acute coronary occlusion. Circulation. 1985;72:1115-1124.
Villanueva FS, Glasheen WP, Sklenar J, Kaul S. Assessment of risk area during coronary occlusion and infarct size after reperfusion with myocardial contrast echocardiography using left and right atrial injections of contrast. Circulation. 1993;88:596-604.
Villanueva FS, Glasheen WP, Sklenar J, Kaul S. Characterization of spatial patterns of flow within the reperfused myocardium by myocardial contrast echocardiography: implication in determining extent of myocardial salvage. Circulation. 1993;88:2596-2606.
Ito H, Tomooka T, Sakai N, Yu H, Higashino Y, Fujii K, Masuyama T, Kitabatake A. Lack of myocardial perfusion immediately after successful thrombolysis: a predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation. 1992;85:1699-1705.
Ito H, Iwakura K, Oh H, Masuyama T, Hori M, Higashino Y, Fujii K, Minamino T. Recovery of coronary micorcirculation after coronary reflow in patients with anterior wall acute myocardial infarction: it correlates to myocardial viability. Circulation. 1995;91:656-662.
Ito H, Yu H, Tomooka T, Masuyama T, Aburaya M, Sakai N, Watada H, Hori M, Higashino Y, Fujii K, Minamino T. Incidence and time course of left ventricular dilation in the early convalescent stage of reperfused anterior wall acute myocardial infarction. Am J Cardiol. 1994;73:539-543.
McKay RG, Pfeffer MA, Pastermak RC, Marikis JE, Come PC, Nakao S, Alderman JK, Ferguson JJ, Safian RD, Grossman W. Left ventricular remodeling after myocardial infarction: a corollary to infarct expansion. Circulation. 1986;74:693-702.
Kaul S, Glasheen W, Ruddy RD, Pandian NG, Weyman AE, Okada RD. The importance of defining left ventricular area at risk in vivo during acute myocardial infarction: an experimental evaluation with myocardial contrast echocardiography. Circulation. 1987;75:1249-1260.
Ito H, Tomooka T, Sakai N, Higashino Y, Fujii K, Katoh O, Masuyama T, Kitabatake A, Minamino T. Time course of functional improvement in stunned myocardium in risk area in patients with reperfused anterior infarction. Circulation. 1993;87:355-362.
Sheehan FH, Bolson EL, Dodge HT, Mathey DG, Schofer J, Woo H-W. Advantages and applications of the centerline method for characterizing regional ventricular function. Circulation. 1986;74:293-305.
Ambrosio G, Weisman HF, Mnnisi JA, Becker LC. Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow. Circulation. 1989;80:1841-1861.
Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications. Circulation. 1990;81:1161-1172.
Hochman JS, Choo H. Limitation of myocardial infarct expansion by reperfusion independent of myocardial salvage. Circulation. 1987;75:299-306.
Rala TE, Gay RG, Goldman S. Importance of venodilation in prevention of left ventricular dilation after chronic large myocardial infarction in rats: a comparison of captopril and hydraalzine. Circ Res. 1989;64:330-337.
Villanueva FS, Glasheen WP, Sklenar J, Jayaweera AR, Kaul S. Successful and reproducible myocardial opacification during two-dimensional echocardiography from right heart injection of contrast. Circulation. 1992;85:1557-1564.