This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Asanuma, T. Articles by Beppu, S. Search for Related Content PubMed PubMed Citation Articles by Asanuma, T. Articles by Beppu, S.

(Circulation. 1997;96:448-453.)
© 1997 American Heart Association, Inc.

Articles

Relationship Between Progressive Microvascular Damage and Intramyocardial Hemorrhage in Patients With Reperfused Anterior Myocardial Infarction

Myocardial Contrast Echocardiographic Study

Toshihiko Asanuma, MD; Kazuaki Tanabe, MD; Koichi Ochiai, MD; Hiroyuki Yoshitomi, MD; Ko Nakamura, MD; Yo Murakami, MD; Kazuya Sano, MD; Toshio Shimada, MD; Rinji Murakami, MD; Shigefumi Morioka, MD; ; Shintaro Beppu, MD

From the Fourth Department of Internal Medicine (T.A., K.T., K.O., H.Y., K.N., Y.M., K.S., T.S., S.M.) and the Emergency Unit (R.M.), Shimane Medical University, Izumo, Japan; and Osaka University School of Medicine (S.B.), Suita, Japan.

Correspondence to Kazuaki Tanabe, MD, The Fourth Department of Internal Medicine, Shimane Medical University, 89-1 Enya-cho, Izumo 693, Japan.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Recent studies indicated that ischemic microvascular damage may be reversible or progressive after coronary reflow. Intramyocardial hemorrhage is a phenomenon that reflects severe microvascular injury. We examined the relationship between temporal changes in microvascular perfusion patterns detected by myocardial contrast echocardiography (MCE) and intramyocardial hemorrhage detected by magnetic resonance imaging (MRI) in patients with acute myocardial infarction (AMI).

Methods and Results The study population consisted of 24 patients with anterior AMI. All patients underwent MCE shortly after reflow and in the chronic stage (a mean of 31 days after reflow). Wall motion score (WMS) was determined as the sum of 16 segmental scores (dyskinetic/akinetic=3 to normal=0) at days 1 and 31. Gradient-echo acquisition and gadolinium-DTPA–enhanced spin-echo MRI were performed within 10 days after reflow. In MCE shortly after reflow, 16 patients (67%) showed contrast enhancement and the other 8 patients (33%) showed a sizable contrast defect. In the chronic stage, a persistent contrast defect was observed in 7 of 8 patients with a contrast defect shortly after reflow. Consistent contrast enhancement was observed in 12 of 16 patients (75%) with contrast enhancement shortly after reflow, indicating that a contrast defect newly appeared in 4 patients (25%). Intramyocardial hemorrhage was detected in 9 patients (38%): 5 of 7 patients with a persistent contrast defect and in all 4 patients with a new appearance of a contrast defect during the chronic stage. The patients without hemorrhage showed a significant improvement in WMS compared with patients with hemorrhage at day 31 (5±5 versus 19±6, P<.0005).

Conclusions These results suggest that irreversible microvascular damage to the ischemic myocardium may cause intramyocardial hemorrhage after reflow, associated with impaired recovery of left ventricular function. Contrast enhancement within the risk area shortly after reflow does not necessarily indicate long-term microvascular salvage.

Key Words: myocardial infarction • microcirculation • magnetic resonance imaging

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Several experimental^{1 2 3 4} and clinical studies^{5 6 7 8} have documented the beneficial effects of reperfusion on the jeopardized myocardium in AMI by limiting the infarct size. Although the improvement in regional function after reperfusion seems to depend on the duration of coronary occlusion, the degree of functional recovery is related to the extent of microvascular damage. Spatial distribution of myocardial blood flow is visualized by MCE, a promising method for evaluating the degree and extent of myocardial microvascular damage.^{9 10 11} Ito et al¹² demonstrated that myocardial perfusion to the infarct area is absent or extremely low shortly after coronary reflow in approximately one fourth of patients with AMI (no-reflow phenomenon) and that functional recovery is worse in patients without MCE reflow than in those with MCE reflow. However, previous studies indicated that ischemic microvascular damage may be reversible¹³ or progressive^{14 15} after coronary reflow. Ito et al¹⁶ and Lim et al¹⁷ recently demonstrated that some patients with MCE reflow immediately after reperfusion showed a late appearance of a contrast defect or decrease in contrast enhancement.

Intramyocardial hemorrhage is a phenomenon that reflects severe microvascular injury, resulting in extravasation of erythrocytes into reperfused myocardium.^{18 19 20} Regardless of whether hemorrhage occurs only in the area of the myocardium already irreversibly injured and predisposed to necrosis, the presence of hemorrhage can be used as a marker for reperfusion injury. Shishido et al²¹ demonstrated in a canine experiment that intramyocardial hemorrhage caused by reperfusion expands gradually after reperfusion, suggesting that the coronary microvascular damage may progress for several hours after coronary reflow. However, the relationship between microvascular damage and intramyocardial hemorrhage has not yet been established in clinical settings. Recent studies have demonstrated the usefulness of MRI for detecting and quantifying the postreperfusion intramyocardial hemorrhage.^{22 23 24 25}

In this study, we examined the relationship between temporal changes in myocardial perfusion patterns detected by MCE (shortly after coronary reflow and about 1 month after reflow) and intramyocardial hemorrhage detected by MRI in patients with anterior AMI.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Population
The study population comprised 24 patients (17 men, 7 women; age, 40 to 76 years; mean age, 62 years) with a first anterior AMI and (1) angiographically documented total or subtotal occlusion in the proximal left anterior descending coronary artery (Thrombosis in Myocardial Infarction Trial [TIMI] grade 2 flow); (2) no significant stenosis in the other coronary arteries (single-vessel disease); (3) adequate two-dimensional echocardiographic images; (4) coronary balloon angioplasty performed within 24 hours after the onset of chest pain; and (5) patency of the infarct-related artery (TIMI grade 3 flow) on coronary angiograms taken shortly after coronary reflow and in the chronic stage (1 month after reflow). Patients with late reperfusion (6 hours after the onset) were included in the study population. The diagnosis of AMI was based on chest pain lasting 30 minutes, ST-segment elevation 2 mm in two contiguous ECG leads, and a greater than threefold increase in serum creatine kinase. Informed consent was obtained from each patient by one of the investigators.

Protocol
Catheterization was performed via the femoral approach in the acute stage of myocardial infarction. Each patient rested in the supine position. After completion of diagnostic coronary angiography, two-dimensional echocardiography was performed to assess the regional wall motion abnormalities before coronary reflow. Two-dimensional echocardiographic images were obtained with a commercially available phased-array system (EUB-555, Hitachi) with a 3.5-MHz transducer. Images were recorded on 1.25-cm videotape with an S-VHS recorder (AG-7355, Panasonic).

Intracoronary nitroglycerin was given to reverse epicardial vasospasm. Coronary balloon angioplasty was performed after the administration of heparin (10 000 to 13 000 units). We did not use thrombolytic agents such as urokinase or tissue plasminogen activator. All patients were given aspirin (81 mg/d) and low-dose heparin (5000 to 10 000 units/d).

MCE was performed about 20 minutes after successful coronary reflow confirmed by coronary angiogram. Two milliliters of sonicated albumin containing microbubbles was injected into the left coronary artery for MCE. Imaging of the apical long-axis view was recorded on videotape, starting at 5 seconds before injection of the contrast agent and lasting until the contrast enhancement was no longer evident with a constant gain setting. After completion of contrast injection into the left coronary artery, the contrast injection was performed into the right coronary artery and the apical long-axis view was recorded. MCE was repeated at least twice on the same view to assess reproducibility. The lead II ECG was continuously monitored during and after MCE.

In all patients, MRI was performed between day 2 and day 10 (mean, day 6) after coronary reflow with a SIGNA 1.5-Tesla system (General Electric). ECG-gated gradient-echo acquisition (flip angle=30 degrees) and Gd-DTPA–enhanced spin-echo MRI were applied for imaging of the heart with the multislice technique (echo time=15 ms, repetition time=RR interval of the ECG). Short-axis images were obtained from apex to base with 7-mm thickness and 3-mm gap. A matrix of 256x192 was used for acquisition, and images were displayed with a 256x256 matrix. The field of view was 320 mm. The fat suppression technique was performed with the use of frequency-selective presaturation. After gradient-echo acquisition and baseline spin-echo MRI scans were performed, a bolus of 0.1 mmol/kg Gd-DTPA was injected intravenously. The images were obtained 10 minutes after Gd-DTPA injection.

Coronary angiography and MCE were repeated at a mean of 31 days (21 to 50 days) after reflow. MCE was performed in the same fashion as in the acute stage. All patients underwent two-dimensional echocardiographic examination at days 1 and 31 after coronary reflow; echocardiographic images were recorded on videotape. Left ventricular regional wall motion was identified either with three longitudinal views (parasternal long-axis, apical four-chamber, apical two-chamber) or three short-axis views (mitral valve level, papillary muscle level, apical level). The left ventricle was divided into 16 segments according to the definition of the American Society of Echocardiography, and wall motion in each segment was evaluated as follows: 3, dyskinetic/akinetic; 2, severe hypokinetic; 1, hypokinetic; and 0, normal. The wall motion score, determined by two independent observers, was represented as the total of scores for each of the 16 segments. In cases of disagreement, a consensus was established with the third observer.

Analysis of MCE Data
Images recorded on videotape were analyzed with the use of an off-line computer system. Abnormal regional wall motion area (dyskinetic, akinetic, severely hypokinetic, and hypokinetic) on the apical long-axis view of the left ventricle was defined as the risk area in echocardiography before coronary reflow. The patients were divided into two groups on the basis of the presence or absence of regional contrast defects within the risk area by MCE performed shortly after reflow and during the chronic stage, respectively. A patchy contrast opacification was not considered a contrast defect in this study.

Analysis of MRI
The patient classification of the presence or absence of intramyocardial hemorrhage was based on the results of the MRI. We considered a low signal intensity area within the risk area by gradient-echo acquisition MRI and a low signal intensity area within a high signal intensity zone by Gd-DTPA–enhanced spin-echo MRI as a marker of intramyocardial hemorrhage (Fig 1). Because gradient-echo acquisition MRI was not performed in 4 of 24 patients, only the results of Gd-DTPA–enhanced spin-echo MRI were used in the 4 patients. In contrast, 1 patient was examined only by gradient-echo acquisition MRI because of an allergy to Gd-DTPA.

View larger version (53K): [in this window] [in a new window]   Figure 1. MRI of left ventricular short-axis view in a patient with reperfused AMI. A low signal intensity area within the risk area by gradient-echo acquisition MRI (A) and a low signal intensity area within a high signal intensity zone by Gd-DTPA–enhanced spin-echo MRI (B) were found, indicating the area that shows intramyocardial hemorrhage (arrows).

Statistical Analysis
All data are expressed as mean±SD. Parameters were compared with the use of commercially available statistical software (StatView, Abacus Concepts). Comparisons between two groups were made with the use of a Mann-Whitney U test and Fisher's exact probability test. Comparisons between results of the initial and delayed studies were made with the use of a Wilcoxon signed rank test. Analysis of the relationship between contrast defect and intramyocardial hemorrhage was performed with the use of Fisher's exact probability test. Differences were considered significant at P<.05.

	Results

Top Abstract Introduction Methods Results Discussion References

 
The average time from onset to reperfusion in the 24 patients was 6 hours (range, 1 to 13 hours). Seven of the 24 patients were reperfused within 3 hours from the onset of symptoms. Fifteen patients developed Q waves in the 12-lead ECG, and the other 9 manifested non– Q-wave myocardial infarction. Coronary balloon angioplasty was not performed in only 1 of the 24 patients because of the coronary reflow after intracoronary nitroglycerin. There was no significant progression of coronary stenosis in either the infarct-related artery or other coronary arteries, and all patients showed TIMI 3 flow in the chronic stage. No ischemic event was observed during the follow-up period in any patient.

Intramyocardial Hemorrhage Detected by MRI
In this study, there was no discrepancy between the findings of gradient-echo acquisition imaging and Gd-DTPA–enhanced spin-echo imaging in 19 patients who were examined by both methods. Intramyocardial hemorrhage within the risk area was detected by MRI in 9 of the 24 patients (38%). The Table summarizes characteristics of patients with and without intramyocardial hemorrhage. There were no differences in age, time from onset to reperfusion, or angiographic collateral grade between patients with and without intramyocardial hemorrhage except for peak serum creatinine phosphokinase and the incidence of Q-wave infarction. All intramyocardial hemorrhage was observed in patients with Q-wave infarction and not observed in patients with non–Q-wave infarction.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Patients With and Without Intramyocardial Hemorrhage

Changes in the wall motion score between the initial and follow-up echocardiographic studies are summarized in Fig 2. There was no difference in the wall motion score between patients with and those without intramyocardial hemorrhage (21±4 versus 20±5, NS) at day 1 after coronary reflow. The patients without intramyocardial hemorrhage showed a significantly greater improvement in the wall motion score compared with those with intramyocardial hemorrhage at day 31 after coronary reflow (5±5 versus 19±6, P<.0005).

View larger version (22K): [in this window] [in a new window]   Figure 2. Changes in the wall motion score between the acute and chronic stages of myocardial infarction. There is no difference in the wall motion score between patients with and those without intramyocardial hemorrhage at day 1 after coronary reflow. Patients without intramyocardial hemorrhage show a significantly greater improvement in wall motion score compared with those with intramyocardial hemorrhage at day 31 after coronary reflow.

Microvascular Damage Detected by MCE
Before coronary reflow, the risk area in the anterior interventricular septum, anterior free wall, and apex was clearly defined as an abnormal regional wall motion area in all study patients. The area of a residual contrast defect was always clearly defined and reproducible.

Significant contrast enhancement was observed within the predetermined risk area shortly after coronary reflow in 16 of the 24 patients (67%). In comparison, a sizable contrast defect was noted in 8 patients (33%) shortly after coronary reflow. In the chronic stage, MCE revealed a persistent contrast defect in 7 of the 8 patients who had the contrast defect shortly after coronary reflow. The contrast defect disappeared in the 1 remaining patient at the later examination. In the chronic stage, consistent contrast enhancement was observed in only 12 of the 16 patients with contrast enhancement shortly after coronary reflow, indicating that the contrast defect newly appeared in 4 patients (Fig 3). Fig 4 shows temporal changes of myocardial contrast echocardiograms in a patient with progressive microvascular damage. The contrast defect was observed in 10 of the 15 patients with Q-wave infarction and in only 1 of the 9 patients with non–Q-wave infarction in the chronic stage. The contrast defect was observed in 43% of patients reperfused within 3 hours and in 47% of patients reperfused >3 hours in the chronic stage.

View larger version (13K): [in this window] [in a new window]   Figure 3. Temporal changes in myocardial perfusion patterns from the acute to the chronic stage. Solid arrows denote patients with intramyocardial hemorrhage; dashed arrows denote those without intramyocardial hemorrhage. In the acute stage, a contrast defect was observed in 8 patients and was not observed in 16 patients. In the chronic stage, a contrast defect was observed in 11 patients and was not observed in 13 patients. A contrast defect newly appeared in 4 patients and disappeared in 1 patient. The presence of a contrast defect during the chronic stage is closely related to the presence of intramyocardial hemorrhage.

View larger version (86K): [in this window] [in a new window]   Figure 4. Myocardial contrast echocardiograms (apical long-axis view) in a patient with anterior myocardial infarction shortly after coronary reflow (A, before contrast injection; B, after contrast injection) and in the chronic stage (C, before contrast injection; D, after contrast injection). Contrast agent was injected into the left coronary artery. Although contrast enhancement was observed within the risk area shortly after reflow, a contrast defect newly appeared 1 month later (arrows). This phenomenon indicates progressive microvascular damage.

Microvascular Damage and Intramyocardial Hemorrhage
Fig 3 also shows the relationship between temporal changes in contrast defects detected by MCE and intramyocardial hemorrhage detected by MRI after coronary reflow. Intramyocardial hemorrhage was detected in 5 of the 7 patients with a persistent contrast defect and in all patients with a new appearance of a contrast defect during the chronic stage. On the other hand, intramyocardial hemorrhage was not found in the patients without a contrast defect during the chronic stage. Therefore, the presence of a contrast defect during the chronic stage was closely related to the presence of intramyocardial hemorrhage.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In this study, MCE was performed in the acute and chronic stages of AMI to assess the effect of coronary reflow. Intramyocardial hemorrhage detected by MRI was closely related to the presence of a contrast defect detected by MCE during the chronic stage. The results of this study suggest that irreversible microvascular damage to the ischemic myocardium may cause intramyocardial hemorrhage after coronary reflow associated with impaired recovery of left ventricular function. Contrast enhancement within the risk area shortly after coronary reflow did not necessarily indicate long-term microvascular salvage.

Intramyocardial Hemorrhage After Coronary Reflow
MRI can characterize the tissue on the basis of changes in relaxation times T1 and T2, which are reflected as changes in image signal intensity. It is well known that MRI is useful for detecting intracranial hemorrhage.^{26 27 28} Gradient-echo acquisition MRI depicts hemorrhage as a low signal intensity area caused by paramagnetic susceptibility effect of deoxyhemoglobin.

Recently, it was reported that MRI may provide a noninvasive method for detecting and quantifying intramyocardial hemorrhage.^{22 23 24 25} Gd-DTPA–enhanced MRI depicts intramyocardial hemorrhage as a low signal intensity area within a high signal intensity zone. Therefore, we used gradient-echo acquisition MRI and Gd-DTPA–enhanced spin-echo MRI to detect intramyocardial hemorrhage in this study. Fujiwara et al²⁹ studied 30 autopsied hearts after thrombolytic therapy. They found that intramyocardial hemorrhage increased gradually after thrombolysis, became moderately or markedly diffuse after 4 hours, and was replaced by fibrosis after 3 to 4 weeks in humans. Therefore, we performed MRI between day 2 and day 10 after coronary reflow.

Although the incidence of intramyocardial hemorrhage after reperfusion was reported in animal preparations^{19 30 31} and autopsy hearts,^{29 32} its incidence in the surviving patients with reperfused AMI remains unclear. Our data revealed that 38% of the patients with anterior AMI after coronary reflow had intramyocardial hemorrhage. However, Waller et al³³ demonstrated that necropsy patients who were treated with angioplasty alone had nonhemorrhagic infarction. The reason for this discrepancy may be related to the time differences in coronary reflow after symptoms became apparent.

Microvascular Damage After Coronary Reflow
Contrast enhancement after coronary reflow reflects the degree of impairment in microvascular function. Coronary reflow as assessed by angiography is not necessarily associated with myocardial contrast enhancement. This condition has been characterized as the no-reflow phenomenon.¹² In our study, 8 of the 24 patients had no-reflow shortly after coronary reflow. Although the mechanism of this phenomenon is not clear,^{34 35 36 37} it has been associated with extensive myocardial necrosis and microvascular damage. However, in 1 of the 8 patients with a contrast defect shortly after coronary reflow, the contrast defect disappeared during the acute to late stage, indicating the improvement of microvascular function. In canine experiments, Bolli et al³⁸ and Triana and Bolli³⁹ documented that the reversible ischemic insult causes prolonged microvascular dysfunction associated with an increase in resting vascular resistance and impairment in vasodilator response. This phenomenon was characterized as microvascular stunning. In our study, 5 of the 7 patients with a persistent contrast defect had intramyocardial hemorrhage, whereas 1 patient in whom the contrast defect disappeared showed no intramyocardial hemorrhage and achieved left ventricular function recovery. This suggests that microvascular stunning may partially explain the reversibility of microvascular function in humans.

Ito et al¹⁶ demonstrated that 7 of 30 patients (23%) with MCE reflow showed a decrease in contrast intensity during the acute to late stage. Lim et al¹⁷ also demonstrated that 4 of 20 patients (20%) with MCE reflow had a late reappearance of a contrast defect. The exact mechanism for the late reappearance of the contrast defect could not be explained. Ambrosio et al¹⁴ showed that the no-reflow area could expand late and that the phenomenon was associated with neutrophil accumulation and capillary plugging late in the course of reperfusion. Kloner et al⁴⁰ also showed the progressive deterioration in coronary vascular reserve, which may be related to neutrophil influx. Recently, Shishido et al²¹ demonstrated in a canine experiment that intramyocardial hemorrhage caused by reperfusion gradually expands from endocardium to epicardium after reperfusion and was almost consistent with the contrast defect area by MCE. In our study, 4 of the 16 patients (25%) without a contrast defect shortly after coronary reflow showed the late appearance of the contrast defect. These patients had intramyocardial hemorrhage, and left ventricular function recovery was worse compared with patients who had contrast enhancement throughout the convalescent stage. Therefore, it is possible that microvascular damage that leads to intramyocardial hemorrhage may progress after coronary reflow.

Limitations of Our Study
The definition of intramyocardial hemorrhage was based on the MRI findings without the histological data. The sensitivity and specificity of our MRI technique to diagnose intramyocardial hemorrhage is not strictly examined because of the small number of autopsies. Lotan et al²⁴ reported that MRI was able to detect intramyocardial hemorrhage as zones of decreased signal intensity in 13 of the 14 dogs (93%) with macroscopic hemorrhage. In 1 dog with macroscopic hemorrhage in which MRI failed to detect reduced signal intensity zones, only a small hemorrhage was observed. Therefore, we believe that our MRI technique has almost the same sensitivity and specificity to diagnose intramyocardial hemorrhage.

Contrast enhancement can be influenced by several factors, including the size and number of microbubbles injected, the injection volume of the contrast medium, and factors affecting ultrasonic reflection such as gain setting, depth of penetration, incident angle, axial and lateral resolution, gray scale compression, and nonlinearity of echo amplitude. The timing of MCE immediately after coronary reflow is another factor that affects the size of the contrast defect.⁴¹ In this study, the same echo plane and same intracoronary injection volume of the sonicated albumin were used to determine the presence or absence of a contrast defect. We could not predict the appearance of intramyocardial hemorrhage after reperfusion because of the small size of the study population. Further studies are necessary to determine the factors that may predict the ultimate outcome of coronary revascularization in the acute stage.

	Selected Abbreviations and Acronyms

 

AMI = acute myocardial infarction Gd-DTPA = gadolinium-diethylenetriaminepentaacetic acid MCE = myocardial contrast echocardiography MRI = magnetic resonance imaging

	Acknowledgments

 
We thank Masakazu Yamagishi, MD, Chief of Clinical Cardiology, National Cardiovascular Center, Suita, for his valuable comments on this work.

	Footnotes

 
Presented in part at the 68th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 13-16, 1995, and published in abstract form in Circulation (1995;92[suppl I]:I-660).

Received November 18, 1996; revision received January 24, 1997; accepted February 2, 1997.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Kloner RA, Ellis SG, Lange R, Braunwald E. Studies of experimental coronary artery reperfusion: effects on infarct size, myocardial function, biochemistry, ultrastructure, and microvascular damage. Circulation. 1983;68(suppl I):I-8-I-15.
   
2. Ellis SG, Henschke CI, Sandor T, Wynne J, Braunwald E, Kloner RA. Time course of functional and biochemical recovery of myocardium salvaged by reperfusion. J Am Coll Cardiol. 1983;1:1047-1055.[Medline] [Order article via Infotrieve]
   
3. Lavallee M, Cox D, Patrick TA, Vatner SF. Salvage of myocardial function by coronary artery reperfusion after 1, 2, and 3 hours after occlusion in conscious dogs. Circ Res. 1983;53:235-247.[Abstract/Free Full Text]
   
4. Bush LR, Buja LM, Samowitz W, Rude RE, Wathen M, Tilton GD, Willerson JT. Recovery of left ventricular segmental function after long-term reperfusion following temporary coronary occlusion in conscious dogs. Circ Res. 1983;53:248-263.[Free Full Text]
   
5. Braunwald E. Myocardial reperfusion, limitation of infarct size, reduction of left ventricular dysfunction, and improved survival: should the paradigm be expanded? Circulation. 1989;79:441-444.[Free Full Text]
   
6. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet. 1986;1:397-402.[Medline] [Order article via Infotrieve]
   
7. Sheehan FH, Braunwald E, Canner P, Dodge HT, Gore J, Van Natta P, Passamani ER, Williams DO, Zaret B, Coinvestigators. The effect of intravenous thrombolytic therapy on left ventricular function: a report on tissue-type plasminogen activator and streptokinase from the Thrombolysis in Myocardial Infarction (TIMI Phase I) Trial. Circulation. 1987;75:817-829.[Abstract/Free Full Text]
   
8. White HD, Norris RM, Brown MA Takayama M, Maslowski A, Bass NM, Ormiston JA, Whitlock T. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med. 1987;317:850-855.[Abstract]
   
9. Kaul S, Gillam LD, Weyman AE. Contrast echocardiography in acute myocardial ischemia, II: the effect of site of injection of contrast agent on the estimation of area at risk for necrosis after coronary occlusion. J Am Coll Cardiol. 1985;6:825-830.[Abstract]
   
10. Kaul S, Glasheen W, Ruddy TD, 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 two-dimensional echocardiography. Circulation. 1987;75:1249-1260.[Abstract/Free Full Text]
    
11. Kaul S, Kelly P, Oliner JD, Glasheen WP, Keller MW, Watson DD. Assessment of regional myocardial blood flow with myocardial contrast two-dimensional echocardiography. J Am Coll Cardiol. 1989;13:468-482.[Abstract]
    
12. Ito H, Tomooka T, Sakai N, Yu H, Higashino Y, Fujii K, Masuyama T, Kitabatake A, Minamino T. 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.[Abstract/Free Full Text]
    
13. Henes CG, Bergmann SR, Perez JE, Sobel BE, Geltman EM. The time course of restoration of nutritive perfusion, myocardial oxygen consumption, and regional function after coronary thrombolysis. Coron Artery Dis. 1990;1:687-696.
    
14. Ambrosio G, Weisman HF, Mannisi JA, Becker LC. Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow. Circulation. 1989;80:1846-1861.[Abstract/Free Full Text]
    
15. Jeremy RW, Links JM, Becker LC. Progressive failure of coronary flow during reperfusion of myocardial infarction: documentation of the no reflow phenomenon with positron emission tomography. J Am Coll Cardiol. 1990;16:695-704.[Abstract]
    
16. Ito H, Iwakura K, Oh H, Masuyama T, Hori M, Higashino Y, Fujii K, Minamino T. Temporal changes in myocardial perfusion patterns in patients with reperfused anterior wall myocardial infarction: their relation to myocardial viability. Circulation. 1995;91:656-662.[Abstract/Free Full Text]
    
17. Lim YJ, Nanto S, Masuyama T, Kohama A, Hori M, Kamada T. Myocardial salvage: its assessment and prediction by the analysis of serial myocardial contrast echocardiograms in patients with acute myocardial infarction. Am Heart J. 1994;128:649-656.[Medline] [Order article via Infotrieve]
    
18. Kloner RA, Ganote CE, Jennings RB. The `no-reflow' phenomenon after temporary coronary occlusion in the dog. J Clin Invest. 1974;54:1496-1508.
    
19. Fishbein MC, Y-Rit J, Lando U, Kanmatsuse K, Mercier JC, Gantz W. The relationship of vascular injury and myocardial hemorrhage to necrosis after reperfusion. Circulation. 1980;62:1274-1279.[Abstract/Free Full Text]
    
20. Kloner RA, Alker KJ. The effect of streptokinase on intramyocardial hemorrhage, infarct size, and the no-reflow phenomenon during coronary reperfusion. Circulation. 1984;70:513-521.[Abstract/Free Full Text]
    
21. Shishido T, Beppu S, Matsuda H, Miyatake K. Progression of intramural hemorrhage in the reperfused area: an experimental study assessed by myocardial contrast echocardiography. Circulation. 1993;88(suppl I):I-402. Abstract.
    
22. McNamara MT, Tscholakoff D, Revel D, Soulen R, Schechtmann N, Botvinick E, Higgins CB. Differentiation of reversible and irreversible myocardial injury by MR imaging with and without gadolinium-DTPA. Radiology. 1986;158:765-769.[Abstract/Free Full Text]
    
23. de Roos A, van Rossum AC, van der Wall E, Postema S, Doornbos J, Matheijssen N, van Dijkman PRM, Visser FC, van Voorthuisen AE. Reperfused and nonreperfused myocardial infarction: diagnostic potential of Gd-DTPA-enhanced MR imaging. Radiology. 1989;172:717-720.[Abstract/Free Full Text]
    
24. Lotan CS, Bouchard A, Cranney GB, Bishop SP, Pohost GM. Assessment of postreperfusion myocardial hemorrhage using proton NMR imaging at 1.5 T. Circulation. 1992;86:1018-1025.[Abstract/Free Full Text]
    
25. Ochiai K, Kitamura J, Tsukihashi H, Ishibashi Y, Murakami Y, Sano K, Shimada T, Morioka S, Kawamitsu H, Sugimura K. The incidence and clinical implication of acute hemorrhagic myocardial infarction detected by MRI. J Am Coll Cardiol. 1995;25(special issue):208A. Abstract.
    
26. Gomori JM, Grossman RI, Goldberg HI, Zimmerman RA, Bilaniuk LT. Intracranial hematomas: imaging by high-field MR. Radiology. 1985;157:87-93.[Abstract/Free Full Text]
    
27. Atlas SW, Mark AS, Grossman RI, Gomori JM. Intracranial hemorrhage: gradient-echo MR imaging at 1.5 T: comparison with spin- echo imaging and clinical applications. Radiology. 1988;168:803-807.[Abstract/Free Full Text]
    
28. Bradley WG Jr. MR appearance of hemorrhage in the brain. Radiology. 1993;189:15-26.[Abstract/Free Full Text]
    
29. Fujiwara H, Onodera T, Tanaka M, Fujiwara T, Wu DJ, Kawai C, Hamashima Y. A clinicopathologic study of patients with hemorrhagic myocardial infarction treated with selective coronary thrombolysis with urokinase. Circulation. 1986;73:749-757.[Abstract/Free Full Text]
    
30. Bresnahan GF, Roberts R, Shell WE, Ross J Jr, Sobel BE. Deleterious effects due to hemorrhage after myocardial reperfusion. Am J Cardiol. 1974;33:82-86.[Medline] [Order article via Infotrieve]
    
31. Higginson LAJ, White F, Heggtveit HA, Sanders TM, Bloor CM, Covell JW. Determinants of myocardial hemorrhage after coronary reperfusion in the anesthetized dog. Circulation. 1982;65:62-69.[Abstract/Free Full Text]
    
32. Garcia-Dorado D, Théroux P, Solares J, Alonso J, Fernandez-Avilés F, Elizaga J, Soriano J, Botas J, Munoz R. Determinants of hemorrhagic infarcts: histologic observations from experiments involving coronary occlusion, coronary reperfusion, and reocclusion. Am J Pathol. 1990;137:301-311.[Abstract]
    
33. Waller BF, Rothbaum DA, Pinkerton CA, Cowley MJ, Linnemeier TJ, Orr C, Irons M, Helmuth RA, Wills ER, Aust C. Status of the myocardium and infarct-related coronary artery in 19 necropsy patients with acute recanalization using pharmacologic (streptokinase, r-tissue plasminogen activator), mechanical (percutaneous transluminal coronary angioplasty) or combined types of reperfusion therapy. J Am Coll Cardiol. 1987;9:785-801.[Abstract]
    
34. Willerson JT, Scales F, Mukherjee A, Platt M, Templeton GH, Fink GS, Buja LM. Abnormal myocardial fluid retention as an early manifestation of ischemic injury. Am J Pathol. 1977;87:159-188.[Abstract]
    
35. Romson JL, Hook BG, Kunkel SL, Abrams GD, Schork A, Lucchesi BR. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation. 1983;67:1016-1023.[Abstract/Free Full Text]
    
36. Olafsson B, Forman MB, Puett DW, Pou A, Cates CU, Friesinger GC, Virmani R. Reduction of reperfusion injury in the canine preparation by intracoronary adenosine: importance of the endothelium and the no-reflow phenomenon. Circulation. 1987;76:1135-1145.[Abstract/Free Full Text]
    
37. Przyklenk K, Kloner RA. `Reperfusion injury' by oxygen-derived free radicals? Effect of superoxide dismutase plus catalase, given at the time of reperfusion, on myocardial infarct size, contractile function, coronary microvasculature, and regional myocardial blood flow. Circ Res. 1989;64:86-96.[Abstract/Free Full Text]
    
38. Bolli R, Triana JF, Jeroudi MO. Prolonged impairment of coronary vasodilation after reversible ischemia: evidence for microvascular `stunning.' Circ Res. 1990;67:332-343.[Abstract/Free Full Text]
    
39. Triana JF, Bolli R. Decreased flow reserve in `stunned' myocardium after a 10-min coronary occlusion. Am J Physiol. 1991;261(Heart Circ Physiol 30):H793-H804.
    
40. Kloner RA, Giacomelli F, Alker KJ, Hale SL, Matthews R, Bellows S. Influx of neutrophils into the walls of large epicardial coronary arteries in response to ischemia/reperfusion. Circulation. 1991;84:1758-1772.[Abstract/Free Full Text]
    
41. Villanueva FS, Glasheen WP, Sklenar J, Kaul S. Characterization of spatial patterns of flow within the reperfused myocardium by myocardial contrast echocardiography: implications in determining extent of myocardial salvage. Circulation. 1993;88:2596-2606.[Abstract/Free Full Text]
    

This article has been cited by other articles:

				A. Kawamoto, H. Iwasaki, K. Kusano, T. Murayama, A. Oyamada, M. Silver, C. Hulbert, M. Gavin, A. Hanley, H. Ma, et al. CD34-Positive Cells Exhibit Increased Potency and Safety for Therapeutic Neovascularization After Myocardial Infarction Compared With Total Mononuclear Cells Circulation, November 14, 2006; 114(20): 2163 - 2169. [Abstract] [Full Text] [PDF]

				E. J. van den Bos, T. Baks, A. D. Moelker, W. Kerver, R.-J. van Geuns, W. J. van der Giessen, D. J. Duncker, and P. A. Wielopolski Magnetic resonance imaging of haemorrhage within reperfused myocardial infarcts: possible interference with iron oxide-labelled cell tracking? Eur. Heart J., July 1, 2006; 27(13): 1620 - 1626. [Abstract] [Full Text] [PDF]

				M. Gick, N. Jander, H.-P. Bestehorn, R.-P. Kienzle, M. Ferenc, K. Werner, T. Comberg, K. Peitz, D. Zohlnhofer, V. Bassignana, et al. Randomized Evaluation of the Effects of Filter-Based Distal Protection on Myocardial Perfusion and Infarct Size After Primary Percutaneous Catheter Intervention in Myocardial Infarction With and Without ST-Segment Elevation Circulation, September 6, 2005; 112(10): 1462 - 1469. [Abstract] [Full Text] [PDF]

				G. A. Krombach, C. B. Higgins, M. Chujo, and M. Saeed Gadomer-enhanced MR Imaging in the Detection of Microvascular Obstruction: Alleviation with Nicorandil Therapy Radiology, August 1, 2005; 236(2): 510 - 518. [Abstract] [Full Text] [PDF]

				R. R. Edelman Contrast-enhanced MR Imaging of the Heart: Overview of the Literature Radiology, September 1, 2004; 232(3): 653 - 668. [Abstract] [Full Text] [PDF]

				S. Kaul and H. Ito Microvasculature in Acute Myocardial Ischemia: Part II: Evolving Concepts in Pathophysiology, Diagnosis, and Treatment Circulation, January 27, 2004; 109(3): 310 - 315. [Full Text] [PDF]

				T. Reffelmann, S. L. Hale, J. S. Dow, and R. A. Kloner No-Reflow Phenomenon Persists Long-Term After Ischemia/Reperfusion in the Rat and Predicts Infarct Expansion Circulation, December 9, 2003; 108(23): 2911 - 2917. [Abstract] [Full Text] [PDF]

				M. Nishino, H.-J. Youn, D. Gheorghevici, C. Zellner, T. M. Chou, K. Sudhir, and R. F. Redberg Effect of Intracoronary Estradiol on Postischemic Microvascular Damage in a Porcine Model: A Myocardial Contrast Echocardiographic Study Angiology, November 1, 2003; 54(6): 701 - 709. [Abstract] [PDF]

				L A Pierard Assessing perfusion and function in acute myocardial infarction: how and when? Heart, July 1, 2003; 89(7): 701 - 703. [Full Text] [PDF]

				L Galiuto, A Lombardo, A Maseri, L Santoro, I Porto, D Cianflone, A G Rebuzzi, and F Crea Temporal evolution and functional outcome of no reflow: sustained and spontaneously reversible patterns following successful coronary recanalisation Heart, July 1, 2003; 89(7): 731 - 737. [Abstract] [Full Text] [PDF]

				S. Genda, T. Miura, T. Miki, Y. Ichikawa, and K. Shimamoto KATP channel opening is an endogenous mechanism of protection against the no-reflow phenomenon but its function is compromised by hypercholesterolemia J. Am. Coll. Cardiol., October 2, 2002; 40(7): 1339 - 1346. [Abstract] [Full Text] [PDF]

				T. Reffelmann and R. A. Kloner Microvascular reperfusion injury: rapid expansion of anatomic no reflow during reperfusion in the rabbit Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1099 - H1107. [Abstract] [Full Text] [PDF]

				E Eeckhout and M.J Kern The coronary no-reflow phenomenon: a review of mechanisms and therapies Eur. Heart J., May 1, 2001; 22(9): 729 - 739. [PDF]

				M. Saeed New Concepts in Characterization of Ischemically Injured Myocardium by MRI Experimental Biology and Medicine, May 1, 2001; 226(5): 367 - 376. [Abstract] [Full Text]

				E. Brochet, D. Czitrom, D. Karila-Cohen, P. Seknadji, M. Faraggi, H. Benamer, P. Aubry, P. G. Steg, and P. Assayag Early changes in myocardial perfusion patterns after myocardial infarction: relation with contractile reserve and functional recovery J. Am. Coll. Cardiol., December 1, 1998; 32(7): 2011 - 2017. [Abstract] [Full Text] [PDF]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Asanuma, T. Articles by Beppu, S. Search for Related Content PubMed PubMed Citation Articles by Asanuma, T. Articles by Beppu, S.