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Hemorrhagic infarction and coronary reperfusion
J
THORAC CARDIOVASC SURG
81:498-501, 1981
Hemorrhagic infarction and coronary reperfusion Coronary ligation experiments were performed on 23 primates. Some of the experiments were followed by reperjusion after periods of occlusion offrom I to 6 hours. Hemorrhage into the infarct was noted in all animals and was greatest following reperjusion after 4 hours of occlusion or longer. Hemorrhage increases the measured infarct size to the point that it is actually larger than that seen with ligation alone. However, this increase is accounted for by the larger amount of intramyocardial hemorrhage. Hemorrhage is greatest in the center of the infarct and decreases at the margins. It appears that hemorrhage occurs into necrotic muscle and does not occur significantly at the margins of the infarct where damage to otherwise viable myocardium might result.
J. Judson McNamara, M.D., Ronald V. Lacro, Michael Vee, B.S., and Gregory T. Smith, Ph.D., Honolulu, Hawaii
Coronary reperfusion experiments have demonstrated that myocardial infarction following coronary artery ligation expands over a few hours from a small zone of central necrosis to involve a potentially viable but nonfunctioning ischemic marginal zone.' Release of the ligature for up to four hours after ligation will result in preservation of myocardium that otherwise would have progressed to infarction. Analogy has been drawn between the reperfusion model in animals and coronary bypass for acute myocardial infarction in human beings. Existing evidence suggests that species differences in myocardial blood flow distribution and the presence of pre-existing coronary occlusive disease (with established collateral flow) limit the precision of the analogy, particularly as regards the extent and temporal evolution of the infarct. Nevertheless, animal reperfusion remains the best experimental model for studying the qualitative effects of coronary artery bypass on myocardial function and viability following acute myocardial infarction. From the Department of Surgery, Queen's Medical Center, and the University of Hawaii, John A. Bums School of Medicine, Honolulu, Hawaii. Supported by National Heart and Lung Institute Grant 5 ROI HI 14571-01. Received for publication July 8, 1980. Accepted for publication Aug. 21, 1980. Address for reprints: J. Judson McNamara, M.D., Department of Surgery, Queen's Medical Center, 1301 Punchbowl St., Honolulu, Hawaii 96813.
498
Reperfusion experiments of 3 hours or longer may result in an apparent increase in infarct size attendant on reperfusion.v 3 It has been suggested that this enlargement of infarct size over that which would have resulted from ligation alone is related to intramyocardial hemorrhage resulting from reperfusion into an area of necrotic myocardium. 4, 5 A concomitant increase in the actual size of the mass of damaged muscle is implied. The present study is composed of a re-review of histologic sections from a larger group of previous experiments to specifically investigate the contribution of hemorrhage to the volume of the infarct. The only animals included were those in which the details of the individual experiment were still on file and all 10 histologic sections were present in the pathology file. Histologic determination of infarct size and estimate of the amount of myocardial hemorrhage indicate a progressive increase in the latter, proportional to the length of occlusion and contributing to the progressive increase in infarct size noted with longer periods of coronary occlusion.
Materials and methods A description of the protocol in the animals included in this study is as follows: Twenty-three monkeys (Macaca cynomulgus}, 3 to 7 kg, had anesthesia initiated with phencyclidine hydrochloride (0.8 to I mg/kg) and maintained with sodium thiopental. They were intubated and connected to a volume respirator (Harvard
0022-5223/81/040498+04$00.40/0 © 1981 The C. V. Mosby Co.
Volume 81 Number 4 April. 1981
Apparatus Co., Inc., Millis, Mass.). A check of blood gases documented adequate respiration. Femoral arterial pressure and electrocardiogram were monitored. Through a left thoracotomy, the heart was suspended in a pericardial cradle. A tourniquet was placed around the left anterior descending coronary artery (LAD) just distal to the first large diagonal branch. The animals were divided into groups according to the duration of coronary occlusion. The LAD was ligated for I hour (four animals), 2 hours (four animals), 4 hours (five animals), 6 hours (five animals), or permanently (five animals). In one control animal, the tourniquet was not tightened during the procedure. Animals in the first four groups had ligature release after the specified period of occlusion. Seven days after the experimental procedure, the animals were anesthetized and hearts were excised and fixed in 10% formalin. Ten transverse sections of equal thickness were made along the major axis of the left ventricle. In this size animal the sections were almost precisely 0.5 ern apart. Slides from each section were stained with hematoxylin and eosin and Gomori's trichrome stain. Morphologic changes associated with ischemia and necrosis and their temporal characterization have been extensively described previously. 1-3 The infarcts generally appeared as a central area with marked degenerative changes, inflammatory cells, fibrin deposition, early scar formation, and varying degrees of intramyocardial hemorrhage. These areas were uniformly a greenish hue with Gomori's trichrome stain. The central areas were bordered by patchy areas of necrosis interspersed with normal muscle fibers. Intramyocardial hemorrhage was a feature of varying prominence in nearly all of the slides viewed and was primarily limited to the central necrotic areas. The areas of infarction were traced with a radiograph pen while the slides were viewed on a microscopic projector. The central area of infarction was marked. The slides were placed in a photographic enlarger and the magnified projections then were traced on thin paper. Planimetry of the tracings and summation of the measured areas allowed calculation of the areas of infarction (AI) and total left ventricular myocardium (A»). Summating the measured areas of each slide provided a numerical expression of the volume of the infarct (!A 1) and the volume of left ventricular myocardium (!Ay). Relating !A1 to !Ay (!A)/!Ay) allowed calculation of the actual percentage of left ventricular myocardium involved in infarction. In addition, each section for each animal was scanned by two observers trained specifically for that purpose (R. Lacro and M. Yee) without prior knowledge of the
Hemorrhagic infarction and coronary reperfusion
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Fig. 1. Mean infarct size expressed as a percent of left Yentricular volume (L. V.) for varying periods of coronary ligation. Infarct sizes after 1 and 2 hours of reperfusion were significantly smaller than those after 6 hours of reperfusion and permanent ligation (p < 0.05). Comparison between other ligation periods did not demonstrate significant difference in infarct size. experimental group to which each animal belonged. Each observer estimated and recorded the percentage of left ventricle that was composed of red cells extravasated into the ischemic myocardium. A total of 230 slides were thus judged. In 26 instances in which interobserver variation exceeded 25% of the estimated value of the percent hemorrhage in the infarct (15 slides), the percent was arbitrated. In all others, the two values for each section were then averaged to give a single estimated percentage of each section of each animal's heart that was comprised of intramyocardial hemorrhage (A H). Summation of all ten sections and comparison with !Ay allowed calculation of an average percentage of left ventricle comprised of hemorrhage for each animal (!AH/!Ay). The percent of infarct involved with hemorrhage was then calculated from (!AH/!Ay)/(!A)/!Ay) yielding !AH/!A). Results
The animal in which the tourniquet was not tightened showed no histologic abnormality. The histologic measure of percentage of the left ventricle infarcted for ligation groups, mean !Ad!Ay, showed a tendency to increase through 6 hours, the percentage with permanent ligation being somewhat smaller than that noted at 6 hours (Fig. I). Animals reperfused at I hour and 2 hours showed statistically significant decrease in !A)/ !Ay (p < 0.05) from those animals whose LAD was ligated permanently. There was no significant difference in !A1/!Ay between animals having reperfusion at 4 hours and 6 hours and those having permanent ligation. Estimation of percentage of infarct involved with
The Journal of
500
McNamara et at.
Thoracic and Cardiovascular Surgery
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Fig. 2. Area of hemorrhage indicated as the proportion of the infarct relative to total volume of the left ventricle (L.V.). Only I and 2 hour ligations and reperfusion showed significant differences as compared with the other three groups (p < 0.05) in each instance.
Fig. 3. Cumulative data on percent of hemorrhage for each period of ligation with or without reperfusion. Mean values for corresponding slides for each ligation period are shown. Slideone is from the base, with sections moving inferiorly to the apex at slide 10.
hemorrhage (lAH/lA j ) showed a tendency to increase with increasing time. Animals with 4 hour and 6 hour ligations appeared to have a greater percentage of hemorrhagic infarct than animals with permanent ligation (Fig. 2). Animals reperfused at I and 2 hours showed a significant decrease in the area of infarct involved with hemorrhage (lAH/lA() when compared to the 4 and 6 hour ligations and the permanent ligations (p < 0.05). However no statistically significant difference was demonstrated between animals reperfused at 4 hours and 6 hours and those having permanent LAD ligation. Also of note is the preponderance of hemorrhage in the central sections, decreasing at margins of the infarct at the base and apex (Fig. 3). Furthermore, in all three groups with prolonged ligation (4 and 6 hours and permanent), two animals in each group demonstrated more. hemorrhage than other animals in each of the groups (Table I). All animals survived the procedure, although two experienced ventricular tachyarrhythmias shortly after ligation. No ventricular arrhythmias occurred in any animals following reperfusion.
cardium if performed within a few hours after the acute occlusion." They also document clearly that significant hemorrhagic infarction does occur with longer periods of coronary occlusion (4 to 6 hours) when compared with reperfusion at I and 2 hours. The estimate of the amount of hemorrhage was at best semiquantitative, but the high agreement between the two observers, the double-blind nature of the study, and the consistency of the resulting data within groups suggest that this was not a major source of error, particularly for intergroup comparisons. Intramyocardial hemorrhage, when it did occur, appeared limited to the central necrotic area of the infarct; very little occurred in the peripheral zone of patchy necrosis. Longer periods of ligation resulted in an exceptionally large amount of hemorrhage in occasional animals. The hemorrhage appeared to increase the area of measured infarct size, although this increase was significant only with longer occlusion periods. This apparent increase may not actually represent more necrotic myocardium but rather an expansion of the center of the infarct by hemorrhage alone. If measurement of infarct size is corrected for the observed areas of hemorrhage, the resulting infarcts appear all the same size or slightly smaller at 4 and 6 hours than those observed with per-
Discussion The data confirm previous work on the ability of coronary reperfusion to salvage ischemic, dying myo-
Volume 81
Hemorrhagic infarction and coronary reperfusion
Number 4 April,1981
501
Table I. Percent of infarct composed of hemorrhage Animal No.
1 hr (%)
2 hr (%)
3 hr (%)
6 hr (%)
Permanently (%)
1 2 3 4 5
17 26 19 0.9
24 9 8 16
21 29 27 21 31
28 35.3 28 29 39
17 18 37 24 44
Mean ± SEM
15.7 ± 4.6
14.3 ± 3.2
25.8 ± 1.8
31.9 ± 2.0
28 ± 4.8
manent ligations. Therefore, it is possible that reperfusion even at 6 hours salvages some myocardium and that the total loss of myocardium is still smaller than it would have been with permanent ligation. Montoya and co-workers? have described hemorrhage into myocardium in patients undergoing revascularization as an emergency for unstable angina. Presumably these individuals had sustained an unrecognized subendocardial infarction. They supported their clinical observation with an experimental study in dogs. The major issue here is whether intramyocardial hemorrhage increases the actual loss of muscle mass. The present study suggests that it does not. Viable myocardium which would be susceptible to injury and subsequent enlargement of the area of infarction lies at the margin of the infarct. Intramyocardial hemorrhage was always central into necrotic muscle and thus added to the bulk of the area of infarction but did not destroy any further viable muscle tissue existing at the infarct margins. These observations suggest that hemorrhage into the infarct probably is not automatically deleterious, and they bear on the issue of revascularization for acute myocardial infarction. REFERENCES SmithGT, SoeterJR, Haston HH, McNamara JJ: Coronary reperfusion in primates. J Clin Invest 54:1420-1427, 1974
2 Lang T, Corday E, Gold H, Meerbaum S, Rubins S, Costantini C, Hirose S, Osher J, Rosen V: Consequences of reperfusion after coronary occlusion. Effects on hemodynamic and regional myocardial metabolic function. Am J Cardiol 33:69-81, 1974 3 Costantini C, Corday E, Lang T, Meerbaum S, Brasch J, Kaplan L, Rubins S, Gold H, Osher J: Revascularization after 3 hours of coronary arterial occlusion. Effects on regional cardiac metabolic function and infarct size. Am J Cardiol 36:368-384, 1975 4 BresnahanGF, Roberts R, Shell WE, Ross J Jr, Sobel BE: Deleteriouseffects due to hemorrhage after myocardial reperfusion. Am J Cardiol 33:82-86, 1974 5 Corday E, Kaplan L, MeerbaumS, Brasch J, Costantini C, Lang T, Gold H, Rubins S, Osher J: Consequences of coronary arterial occlusion on remote myocardium. Effects of occlusion and reperfusion. Am J Cardiol 36:385-394, 1975 6 Maroko PR, Libby P, Ginks WR, Bloor CM, Shell WE, Sobel BE, Ross J Jr: Coronary artery reperfusion. I. Early effects on local myocardialfunction and the extent of myocardial necrosis. J Clin Invest 51:2710-2716, 1972 7 Montoya A, Mulet J, Pifarre R, Brynjolfsson G, Moran JM, Sullivan HJ, Gunnar RM: Hemorrhagicinfarct following myocardial revascularization. J THORAC CARDIOVASC SURG 75:206-212, 1978
THORAC CARDIOVASC SURG
81:498-501, 1981
Hemorrhagic infarction and coronary reperfusion Coronary ligation experiments were performed on 23 primates. Some of the experiments were followed by reperjusion after periods of occlusion offrom I to 6 hours. Hemorrhage into the infarct was noted in all animals and was greatest following reperjusion after 4 hours of occlusion or longer. Hemorrhage increases the measured infarct size to the point that it is actually larger than that seen with ligation alone. However, this increase is accounted for by the larger amount of intramyocardial hemorrhage. Hemorrhage is greatest in the center of the infarct and decreases at the margins. It appears that hemorrhage occurs into necrotic muscle and does not occur significantly at the margins of the infarct where damage to otherwise viable myocardium might result.
J. Judson McNamara, M.D., Ronald V. Lacro, Michael Vee, B.S., and Gregory T. Smith, Ph.D., Honolulu, Hawaii
Coronary reperfusion experiments have demonstrated that myocardial infarction following coronary artery ligation expands over a few hours from a small zone of central necrosis to involve a potentially viable but nonfunctioning ischemic marginal zone.' Release of the ligature for up to four hours after ligation will result in preservation of myocardium that otherwise would have progressed to infarction. Analogy has been drawn between the reperfusion model in animals and coronary bypass for acute myocardial infarction in human beings. Existing evidence suggests that species differences in myocardial blood flow distribution and the presence of pre-existing coronary occlusive disease (with established collateral flow) limit the precision of the analogy, particularly as regards the extent and temporal evolution of the infarct. Nevertheless, animal reperfusion remains the best experimental model for studying the qualitative effects of coronary artery bypass on myocardial function and viability following acute myocardial infarction. From the Department of Surgery, Queen's Medical Center, and the University of Hawaii, John A. Bums School of Medicine, Honolulu, Hawaii. Supported by National Heart and Lung Institute Grant 5 ROI HI 14571-01. Received for publication July 8, 1980. Accepted for publication Aug. 21, 1980. Address for reprints: J. Judson McNamara, M.D., Department of Surgery, Queen's Medical Center, 1301 Punchbowl St., Honolulu, Hawaii 96813.
498
Reperfusion experiments of 3 hours or longer may result in an apparent increase in infarct size attendant on reperfusion.v 3 It has been suggested that this enlargement of infarct size over that which would have resulted from ligation alone is related to intramyocardial hemorrhage resulting from reperfusion into an area of necrotic myocardium. 4, 5 A concomitant increase in the actual size of the mass of damaged muscle is implied. The present study is composed of a re-review of histologic sections from a larger group of previous experiments to specifically investigate the contribution of hemorrhage to the volume of the infarct. The only animals included were those in which the details of the individual experiment were still on file and all 10 histologic sections were present in the pathology file. Histologic determination of infarct size and estimate of the amount of myocardial hemorrhage indicate a progressive increase in the latter, proportional to the length of occlusion and contributing to the progressive increase in infarct size noted with longer periods of coronary occlusion.
Materials and methods A description of the protocol in the animals included in this study is as follows: Twenty-three monkeys (Macaca cynomulgus}, 3 to 7 kg, had anesthesia initiated with phencyclidine hydrochloride (0.8 to I mg/kg) and maintained with sodium thiopental. They were intubated and connected to a volume respirator (Harvard
0022-5223/81/040498+04$00.40/0 © 1981 The C. V. Mosby Co.
Volume 81 Number 4 April. 1981
Apparatus Co., Inc., Millis, Mass.). A check of blood gases documented adequate respiration. Femoral arterial pressure and electrocardiogram were monitored. Through a left thoracotomy, the heart was suspended in a pericardial cradle. A tourniquet was placed around the left anterior descending coronary artery (LAD) just distal to the first large diagonal branch. The animals were divided into groups according to the duration of coronary occlusion. The LAD was ligated for I hour (four animals), 2 hours (four animals), 4 hours (five animals), 6 hours (five animals), or permanently (five animals). In one control animal, the tourniquet was not tightened during the procedure. Animals in the first four groups had ligature release after the specified period of occlusion. Seven days after the experimental procedure, the animals were anesthetized and hearts were excised and fixed in 10% formalin. Ten transverse sections of equal thickness were made along the major axis of the left ventricle. In this size animal the sections were almost precisely 0.5 ern apart. Slides from each section were stained with hematoxylin and eosin and Gomori's trichrome stain. Morphologic changes associated with ischemia and necrosis and their temporal characterization have been extensively described previously. 1-3 The infarcts generally appeared as a central area with marked degenerative changes, inflammatory cells, fibrin deposition, early scar formation, and varying degrees of intramyocardial hemorrhage. These areas were uniformly a greenish hue with Gomori's trichrome stain. The central areas were bordered by patchy areas of necrosis interspersed with normal muscle fibers. Intramyocardial hemorrhage was a feature of varying prominence in nearly all of the slides viewed and was primarily limited to the central necrotic areas. The areas of infarction were traced with a radiograph pen while the slides were viewed on a microscopic projector. The central area of infarction was marked. The slides were placed in a photographic enlarger and the magnified projections then were traced on thin paper. Planimetry of the tracings and summation of the measured areas allowed calculation of the areas of infarction (AI) and total left ventricular myocardium (A»). Summating the measured areas of each slide provided a numerical expression of the volume of the infarct (!A 1) and the volume of left ventricular myocardium (!Ay). Relating !A1 to !Ay (!A)/!Ay) allowed calculation of the actual percentage of left ventricular myocardium involved in infarction. In addition, each section for each animal was scanned by two observers trained specifically for that purpose (R. Lacro and M. Yee) without prior knowledge of the
Hemorrhagic infarction and coronary reperfusion
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Fig. 1. Mean infarct size expressed as a percent of left Yentricular volume (L. V.) for varying periods of coronary ligation. Infarct sizes after 1 and 2 hours of reperfusion were significantly smaller than those after 6 hours of reperfusion and permanent ligation (p < 0.05). Comparison between other ligation periods did not demonstrate significant difference in infarct size. experimental group to which each animal belonged. Each observer estimated and recorded the percentage of left ventricle that was composed of red cells extravasated into the ischemic myocardium. A total of 230 slides were thus judged. In 26 instances in which interobserver variation exceeded 25% of the estimated value of the percent hemorrhage in the infarct (15 slides), the percent was arbitrated. In all others, the two values for each section were then averaged to give a single estimated percentage of each section of each animal's heart that was comprised of intramyocardial hemorrhage (A H). Summation of all ten sections and comparison with !Ay allowed calculation of an average percentage of left ventricle comprised of hemorrhage for each animal (!AH/!Ay). The percent of infarct involved with hemorrhage was then calculated from (!AH/!Ay)/(!A)/!Ay) yielding !AH/!A). Results
The animal in which the tourniquet was not tightened showed no histologic abnormality. The histologic measure of percentage of the left ventricle infarcted for ligation groups, mean !Ad!Ay, showed a tendency to increase through 6 hours, the percentage with permanent ligation being somewhat smaller than that noted at 6 hours (Fig. I). Animals reperfused at I hour and 2 hours showed statistically significant decrease in !A)/ !Ay (p < 0.05) from those animals whose LAD was ligated permanently. There was no significant difference in !A1/!Ay between animals having reperfusion at 4 hours and 6 hours and those having permanent ligation. Estimation of percentage of infarct involved with
The Journal of
500
McNamara et at.
Thoracic and Cardiovascular Surgery
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Fig. 2. Area of hemorrhage indicated as the proportion of the infarct relative to total volume of the left ventricle (L.V.). Only I and 2 hour ligations and reperfusion showed significant differences as compared with the other three groups (p < 0.05) in each instance.
Fig. 3. Cumulative data on percent of hemorrhage for each period of ligation with or without reperfusion. Mean values for corresponding slides for each ligation period are shown. Slideone is from the base, with sections moving inferiorly to the apex at slide 10.
hemorrhage (lAH/lA j ) showed a tendency to increase with increasing time. Animals with 4 hour and 6 hour ligations appeared to have a greater percentage of hemorrhagic infarct than animals with permanent ligation (Fig. 2). Animals reperfused at I and 2 hours showed a significant decrease in the area of infarct involved with hemorrhage (lAH/lA() when compared to the 4 and 6 hour ligations and the permanent ligations (p < 0.05). However no statistically significant difference was demonstrated between animals reperfused at 4 hours and 6 hours and those having permanent LAD ligation. Also of note is the preponderance of hemorrhage in the central sections, decreasing at margins of the infarct at the base and apex (Fig. 3). Furthermore, in all three groups with prolonged ligation (4 and 6 hours and permanent), two animals in each group demonstrated more. hemorrhage than other animals in each of the groups (Table I). All animals survived the procedure, although two experienced ventricular tachyarrhythmias shortly after ligation. No ventricular arrhythmias occurred in any animals following reperfusion.
cardium if performed within a few hours after the acute occlusion." They also document clearly that significant hemorrhagic infarction does occur with longer periods of coronary occlusion (4 to 6 hours) when compared with reperfusion at I and 2 hours. The estimate of the amount of hemorrhage was at best semiquantitative, but the high agreement between the two observers, the double-blind nature of the study, and the consistency of the resulting data within groups suggest that this was not a major source of error, particularly for intergroup comparisons. Intramyocardial hemorrhage, when it did occur, appeared limited to the central necrotic area of the infarct; very little occurred in the peripheral zone of patchy necrosis. Longer periods of ligation resulted in an exceptionally large amount of hemorrhage in occasional animals. The hemorrhage appeared to increase the area of measured infarct size, although this increase was significant only with longer occlusion periods. This apparent increase may not actually represent more necrotic myocardium but rather an expansion of the center of the infarct by hemorrhage alone. If measurement of infarct size is corrected for the observed areas of hemorrhage, the resulting infarcts appear all the same size or slightly smaller at 4 and 6 hours than those observed with per-
Discussion The data confirm previous work on the ability of coronary reperfusion to salvage ischemic, dying myo-
Volume 81
Hemorrhagic infarction and coronary reperfusion
Number 4 April,1981
501
Table I. Percent of infarct composed of hemorrhage Animal No.
1 hr (%)
2 hr (%)
3 hr (%)
6 hr (%)
Permanently (%)
1 2 3 4 5
17 26 19 0.9
24 9 8 16
21 29 27 21 31
28 35.3 28 29 39
17 18 37 24 44
Mean ± SEM
15.7 ± 4.6
14.3 ± 3.2
25.8 ± 1.8
31.9 ± 2.0
28 ± 4.8
manent ligations. Therefore, it is possible that reperfusion even at 6 hours salvages some myocardium and that the total loss of myocardium is still smaller than it would have been with permanent ligation. Montoya and co-workers? have described hemorrhage into myocardium in patients undergoing revascularization as an emergency for unstable angina. Presumably these individuals had sustained an unrecognized subendocardial infarction. They supported their clinical observation with an experimental study in dogs. The major issue here is whether intramyocardial hemorrhage increases the actual loss of muscle mass. The present study suggests that it does not. Viable myocardium which would be susceptible to injury and subsequent enlargement of the area of infarction lies at the margin of the infarct. Intramyocardial hemorrhage was always central into necrotic muscle and thus added to the bulk of the area of infarction but did not destroy any further viable muscle tissue existing at the infarct margins. These observations suggest that hemorrhage into the infarct probably is not automatically deleterious, and they bear on the issue of revascularization for acute myocardial infarction. REFERENCES SmithGT, SoeterJR, Haston HH, McNamara JJ: Coronary reperfusion in primates. J Clin Invest 54:1420-1427, 1974
2 Lang T, Corday E, Gold H, Meerbaum S, Rubins S, Costantini C, Hirose S, Osher J, Rosen V: Consequences of reperfusion after coronary occlusion. Effects on hemodynamic and regional myocardial metabolic function. Am J Cardiol 33:69-81, 1974 3 Costantini C, Corday E, Lang T, Meerbaum S, Brasch J, Kaplan L, Rubins S, Gold H, Osher J: Revascularization after 3 hours of coronary arterial occlusion. Effects on regional cardiac metabolic function and infarct size. Am J Cardiol 36:368-384, 1975 4 BresnahanGF, Roberts R, Shell WE, Ross J Jr, Sobel BE: Deleteriouseffects due to hemorrhage after myocardial reperfusion. Am J Cardiol 33:82-86, 1974 5 Corday E, Kaplan L, MeerbaumS, Brasch J, Costantini C, Lang T, Gold H, Rubins S, Osher J: Consequences of coronary arterial occlusion on remote myocardium. Effects of occlusion and reperfusion. Am J Cardiol 36:385-394, 1975 6 Maroko PR, Libby P, Ginks WR, Bloor CM, Shell WE, Sobel BE, Ross J Jr: Coronary artery reperfusion. I. Early effects on local myocardialfunction and the extent of myocardial necrosis. J Clin Invest 51:2710-2716, 1972 7 Montoya A, Mulet J, Pifarre R, Brynjolfsson G, Moran JM, Sullivan HJ, Gunnar RM: Hemorrhagicinfarct following myocardial revascularization. J THORAC CARDIOVASC SURG 75:206-212, 1978