Nutrient Mlyocardial Blood Flow in Experimental Myocardial Ischemia Effects of Intraaortic Balloon Counterpulsation and Coronary Reperfusion By VIRENDER K. SAINI, M.D., WILLIAM B. HOOD, JR., M.D., HERBERT B. HECHTMAN, M.D.,
AND
ROBERT L. BERGER, M.D.
SUMMARY This experimental study was designed to evaluate the effect of intraaortic balloon pumping (IABP) upon nutrient myocardial blood flow (NMBF) following acute myocardial ischemia in dogs, but also to determine whether IABP improves NMBF following revascularization. Localized myocardial ischemia was produced by ligation of one or two small branches of the circumflex coronary artery combined with a three hour snare occlusion of the left anterior descending coronary artery distal to the first septal branch. NMBF was measured by NaIl31 washout at three points corresponding to the peripheral, intermediate, and central zones of the infarct. Occlusion of the coronary arteries reduced NMBF. Release of occlusion after three hours, or the equivalent of coronary artery revascularization, increased NMBF but did not restore it to control levels. The increase in flow was more marked in the peripheral zones of ischemia. IABP increased NMBF significantly both during and after release of occlusion. The effect was sustained after cessation of IABP only when the latter was maintained during the period of reperfusion. The results indicate that NMBF, defined by washout of a locally injected tracer, was improved by both IABP and reperfusion. The beneficial effect was maximal when the two techniques were combined.
EMERGENCY AORTOCORONARY BYPASS revascularization has been employed in patients with acute myocardial ischemia and infarction in an attempt to reperfuse the ischemic myocardium and to permit recovery of left ventricular function.,
we measured the effects of both IABP and revascularization, separately and in combination, upon nutrient myocardial blood flow (NMBF) in an experimental canine ischemic preparation. It was shown that NMBF, defined by washout of a locally injected tracer, was improved by both interventions, and was maximal when they were used
Another method of reclaiming ischemic myocardium is the use of intraaortic balloon pumping (IABP), which decreases left ventricular workload and increases coronary perfusion pressure. This technique has been employed with some success in treating patients with cardiogenic shock due to acute myocardial infarction.5 It has been suggested from experimental studies that IABP promotes the development of functional coronary collaterals6 and may reduce the size of infarcts in experimental animals.7-9 However, others were not able to reproduce these
simultaneously. Methods Studies were carried out in 22 mongrel dogs with a mean weight of 30.9 ± 2.1 (SEM) kg. Animals were anesthetized with 25 mg/kg of sodium pentobarbital. Respiration was maintained after endotracheal intubation by a Harvard respirator with a 40% oxygen mixture. The heart was exposed through a left thoracotomy. A grossly visible confluent area of acute myocardial ischemia was produced by ligation of one to two small peripheral branches of the circumflex coronary artery, and then temporary occlusion of the left anterior descending coronary artery (LAD) distal to the first perforator branch with a removable snare. This technique permitted a staged temporary occlusion13 and was designed to simulate clinical coronary occlusion followed by revascularization. A schematic drawing of the experimental preparation is shown in figure 1. Monitoring of aortic and left atrial pressures and of cardiac output was carried out. Pressures were obtained using catheters connected to Statham P23Db transducers, and were recorded on a Hewlett-Packard multichannel recorder. The zero level for pressure measurements was set at the mid-chest. Serial cardiac output determinations were made using the indicator dilution technique, by injecting in-
salutary results.0102 In an effort to clarify further the role of these two forms of therapy in ameliorating myocardial ischemia, From the Department of Cardiothoracie Surgery and the Medical Service, Boston City Hospital and Boston University Medical Center, Boston, Massachusetts. Supported by the Norwich Thoracic Research Fund, USPHS Grants HL 71-2498, HL 14646, and HE 07299, and American Heart Association Grant 74-1013. Address for reprints: Robert L. Berger, M. D., University Hospital, 75 East Newton Street, Boston, Massachusetts 02118. Received May 27, 1975; revision accepted for publication July 3, 1975.
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through the femoral artery and positioned in the descending thoracic aorta distal to the left subelavian artery. The animals were divided into three groups: Group I (control nine dogs). Myocardial ischemia was produced as described above and the LAD snare was -
Figure 1 Diagrammatic representation of the experimental model of (hatched area). Nutritional myocardial blood by NaI'31 injection at three points (A, B, C), corresponding to the peripheral, intermediate and central zones of ischemia. L.A.D. = left anterior descending coronary artery.
coronary ischemia flow was measured
docyanine green dye into the right atrium and sampling from the aorta. Nutrient myocardial blood flow was measured with the NaIl3` washout technique" by injecting 10 gCi of the isotope 3 mm into the myocardium in a volume of 0.1 cc with a 25 gauge needle (fig. 1). Radioactivity over the site of the injection was measured with a Picker Nuclear Omniprobe Model 12830-A through a Baird Atomic analog rate meter counter and recorded on a Gilson direct writing linear recorder. The difference between extrapolated background and the points along the washout curve were replotted on semilogarithmic paper. NMBF was calculated in ml/min/100 gm myocardium.`5 Sequential injections and measurements of NMBF were carried out at three preselected sites, A, B and C, which corresponded to peripheral, intermediate and central portions of the ischemic zone (fig. 1). An AVCO* helium-driven pumping system utilizing a three segmented balloon mounted on a 12 or 14F catheter was employed in these studies. The circuitry is designed to permit triggering of inflation and deflation from the electrocardiogram. Balloons of either 20 or 30 cc capacity, depending upon the size of the animal, were inserted Everett Research Laboratory, Everett, Mass.
released after three hours of occlusion. This model is analogous to acute coronary occlusion and early myocardial revascularization. NMBF was measured prior to occlusion, ten minutes after coronary occlusion, just prior to release of the LAD snare and ten minutes after restoration of flow through the coronary artery (fig. 2). Group II (six dogs). Coronary artery occlusion was carried out as in the controls. IABP was initiated ten minutes after the application of the LAD snare (following NMBF measurement) and was discontinued ten minutes prior to reflow to LAD. This sequence is analogous to the clinical situation in which IABP is used in the preoperative phase but only prior to coronary revascularization. NMBF was measured, as in the controls, before and ten minutes after the coronary occlusion, ten minutes prior to and ten minutes following cessation of IABP and finally ten minutes after release of the LAD occlusion (fig. 2). Group III (seven dogs). This group was treated similarly to group II with the exception that IABP support was continued after the release of the LAD snare. In the clinical setting this sequence is analogous to pre and postrevascularization circulatory support. NMBF was measured before and ten minutes after coronary occlusion, after three hours of IABP, ten minutes following release of occlusion with IABP still in effect, and finally ten minutes after stopping IABP (fig. 2). Statistical comparisons were carried out using Student's ttest, using paired data when appropriate. Results
Occlusion of the left anterior descending coronary resulted in appearance of a noncontracting cyanotic area of ischemia on the anterior surface of the left ventricle. However, only modest changes in hemodynamic measurements were noted after coronary occlusion; severe cardiac failure or cardiogenic artery
[3 Coronary M IABP 131I
Occlusion
Injection
GROUP I
_..
..........................
GROUP
ll
I
GROUP 0
4
2
3
HOURS
Figure 2 Experimental protocol showing timing of coronary occlusion and reflow for groups I-II1, and timing of IABP in groups II and III.
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absent. Cardiac output fell from 103 ± 5 7 ml/min/kg (P < 0.01), and left atrial mean pressure rose from 8.4 ± 0.5 to 11.3 ± 0.6 mm Hg (P < 0.001), while aortic mean pressure did not change significantly (121 ± 4 mm Hg before and 115 ± 5 mm Hg after occlusion). With institution of IABP, evidence of diastolic augmentation was documented in each animal in groups II and III from the aortic pressure tracings. Measurements of NMBF in the three groups of animals are shown in table 1. In group I (control) animals, NMBF was markedly depressed at all three points of measurement following coronary occlusion.
of IABP. The response was similar to that seen in group II animals, which, up to this point in time, had been treated in identical fashion to group III animals (table 1). Release of the coronary occlusion, with continuation of IABP, resulted in a marked rise in NMBF, especially in the more peripheral zones of the ischemic area (points A and B). After cessation of IABP, NMBF again declined, but the values were, in this case, significantly higher than in control animals during reflow.
The values remained at this low level during the three hours of occlusion, but then rose significantly following release of the snare. However, the flow values were still reduced below the control state. Point C in the center of the ischemic zone showed the lowest flow values, while at points A and B, or the more peripheral portions of the infarct, the flows were higher. In group II animals coronary occlusion likewise produced a marked fall in NMBF in all three zones of ischemia (table 1). However, after three hours of IABP, a significant increase in NMBF occurred at all three points in comparison to control animals. When IABP was discontinued with the coronary occlusion still in effect a second fall in NMBF was observed. When the LAD snare was released NMBF rose again, but the values were not significantly different from those observed with reflow in the control animals. In group III animals NMBF fell following application of the LAD snare, but rose again after three hours
injury and reduced contractile performance`6 of the
shock to 87
were
±
Occlusion of zone
a
Discussion coronary artery results in ischemic
of myocardium supplied by the stenosed vessel.
In the early phases of ischemia these functional
changes are readily reversible with reperfusion.'6 Electron microscopic and histochemical studies reveal that, for a period up to 20 minutes after coronary occlusion, irreversible injury does not take place.'7-19
Furthermore, even when ischemia is prolonged and a central zone of irreversible ischemic injury is present, the margins of the infarct may contain viable myocardium. Data have been obtained suggesting that a number of metabolic and hemodynamic interventions,20 among them intraaortic balloon pumping,7-9
reduce ischemic damage. The question of how long myocardium may remain ischemic and yet be restored to normal function following revascularization has not yet been fully answered. From limited experience with emergency revascularization procedures in patients, there is may
Table 1 Nutrient Myocardial Blood Flow (ml/min/100 gm myocardium) Control Group
I
Point
A B C
II
III
A B C
A B C
preocclusion
72.3 73.7 69.7
77.8 69.5 64.3 90.9 91.3 91.7
8.4§ 7.4 7.3
-
-
-
8.8 8.4 6.8 53.3 5.3 9.6
Occlusion (10 min)
Occlusion (3 hr)
15.7 * 2.2t 14.8 i 2.4 11.1 i 2.0
1a.0 3 2.4t 1.3* 9.9 7.2 i 1.4 Occlusion plus IABP
12.6 i 3.1 11.2 2.2 12.4 1.8
10.8 11.6 10.4
-
-
1.4 2.7 2.5
335.0
8.9*1 3.7*1 - 4.0*1 Occlusion plus IABP
23.3 24.8 24.1 18.2 16.5
-
-
-
-
Reflow
38.3 i 3.9*t 39.7 4-3*t 24.7 4.7*
Occlusion minus IABP 19.2 - 4.8* 16.2 - 3.8* 13.6 - 3.4
2.1*1l
2.4*1 2.71
43.7 42.3 32.2
Reflow plus IABP 73.1 - 8.1*1t 70.4 - 8.3*1 54.6 - 11.0*t
9.0*
i 8.1* 8.0
i 7.0*t1 7.7*1 49.7 i 9.4*1 68.7
59.9
All occlusion (10 min) values differ significanitly (P < 0.03) from control preocclusion. Intragroup comparisons (paired differences): *P < 0.03, compared to postocclusioii (10 niin). tP < 0.05, compared to point C. Intergroup comparisons (unpaired differences): JP < 0.05, compared to group I.
§Expressed
as mean- SEM.
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52,
December 1975
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evidence that restoration of function may be possible after hours3 4 or even days of ischemia.21 Most experimental studies, however, indicate that much briefer periods of reduced blood flow are critical. In the normal canine ventricle, temporary coronary occlusion lasting from forty-five minutes'9 to three hours22 causes permanent myocardial damage. Furthermore, reperfusion after five hours of ischemia produces variable results, with some animals showing reduction of ultimate infarct size and others hemorrhage into the ischemic zone with infarct extension.23 The present study provides additional evidence that coronary occlusion for three hours produces lasting deleterious effects upon the coronary circulation in that reperfusion provides only partial benefit and does not restore NMBF to preocclusion levels. The mechanism for these findings is uncertain, but may relate to tissue edema or capillary endothelial swelling, analogous to the no-reflow phenomenon in other tissues.24 Evidence available to date suggests that IABP is effective in reducing infarct size7`9 and in lowering mortality2` in experimental coronary occlusion. This may be due in part to reduction of myocardial oxygen demands by lowering afterload, and also, in unanesthetized animals, cardiac rate.26 In addition, some authors have suggested that coronary collateral flow may be improved as a result of augmentation of diastolic pressure.ff 7 These conclusions were, however, based upon indirect methods of assessing collateralization, including postmortem coronary angiograms5 and detection of increased coronary blood flow in unoccluded coronary arteries supplying normal myocardium adjacent to an infarct.7 Attempts to measure changes in NMBF induced by IABP have thus far failed to demonstrate conclusively that collateral flow is increased by this intervention."' 12 In the study performed by Reneman et al.,1 washout of indicator injected into the center of the ischemic zone was not increased significantly by a three-hour period of IABP. In the present study, a modest increase in NMBF was observed in the infarct center with IABP. Changes resulting from IABP were, however, more marked in the peripheral and intermediate zones of ischemia, especially in the postreperfusion period. In the study performed by Shaw et al.,12 a brief period of IABP (30 min) did not significantly improve flow as measured by microsphere techniques in either the center or border zones of ischemic myocardium, although the reduced ratio of endocardial to epicardial blood flow in the ischemic border zone was significantly increased by IABP. The disparity between the latter study and the present one might be explained by differences in the duration of IABP.
In the present study NMBF was assayed by the injection of sodium radioiodide directly into the myocardium. The rate of disappearance of this indicator has been shown to reflect local myocardial blood flow."' Other investigators'5' 27 have used this technique with various indicators to study the local circulation in the myocardium, and although the method may not be precisely quantitative in terms of providing absolute blood flow values, it is possible to detect directional changes of flow.15 Three points of measurement distributed from the center to the margins of the infarct were selected in order to evaluate changes in the NMBF in different zones of the infarct. In control animals release of occlusion after three hours of ischemia, or the equivalent of coronary artery revascularization, increased NMBF but did not restore it to control. In animals treated with IABP, the increase in NMBF was most marked in the intermediate and peripheral zones of the infarct. However, the increment in blood flow produced by IABP which was terminated prior to reflow was limited to the duration of the assist and did not influence the levels of NMBF after reperfusion. When IABP was maintained into the postreperfusion period, high values of NMBF were observed, and, when IABP was finally withdrawn, the increased flow persisted at higher levels than those observed in control studies. Though extrapolation of these animal experiments to the clinical setting in patients with myocardial infarction must be done with caution, these data may have clinical implications. It may be that intraaortic balloon pumping should be carried out in patients for prolonged periods of time following coronary revascularization procedures to permit maximal effects upon nutrient myocardial blood flow and presumably also upon recovery of potentially viable
myocardium. Acknowledgment We should like to express our appreciation to J. Patel, M.D., R. Diorio, B. Ugarte, M. Cassidy, R. Rosen and W. Wright for their asssistance in carrying out these studies.
References 1. SCANLON PJ, NEMICKAS R, TOBIN JR JR, ANDERSON W, MONTOYA A, PIFARRE R: Myocardial revascularization during acute phase of myocardial infarction. JAMA 218: 207, 1971 2. MUNDTH ED, BUCKLEY MJ, DAGGETT WM, SANDERS CA, AUSTEN WG: Surgery for complications of acute myocardial infarction. Circulation 45: 1279, 1972 3. CHATTERJEE K, SWAN HJ, PARMLEY WW, SUSTAITA H, MARCUS H, MATLOFF J: Depression of left ventricular function due to acute myocardial ischemia and its reversal following aortocoronary saphenous-vein-bypass. N Engl J Med 286: 1117, 1972
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4. CHEANVECHAI C, EFFLER DB, Loop FD, GROVES LK, SHELDON WC, RAZARI M, SONES M: Emergency myocardial revascularization. Am J Cardiol 32: 901, 1973 5. SCHEIDT S, WILNER G, MUELLER H, SUMMERS D, LESCH M, WOLFF G, KRAKAUER J, RUBENFIRE M, FLEMING P, NooN G,
6.
7.
8.
9.
10.
11.
12.
13. 14.
OLDHAM N, KILLIP T, KANTROWITZ A: Intra-aortic balloon counterpulsation in cardiogenic shock. Report of a cooperative clinical trial. N Engl J Med 288: 979, 1973 JACOBEY JA, TAYLOR WJ, SMITH GT, GORLIN R, HARKEN DE: A new therapeutic approach to acute coronary occlusion. II. Opening dormant coronary collateral channels by counterpulsation. Am J Cardiol 11: 218, 1963 RoSENSWuEIc J, CHATTERJEE S: Mechanical augmentation of coronary circulation in the ischemic heart: Angiographic and hemodynamic correlation with prolonged survival. J Thorac Cardiovasc Surg 54: 839, 1968 GOLDFARB D, FRIESINGER GC, CONTI CR, BROWN BG, GOTT VL: Preservation of myocardial viability by diastolic augmentation after ligation of the coronary artery in dogs. Surgery 63: 320, 1968 MAROKO PR, BERNSTEIN EF, LIBBY P, DELARIA GA, COVELL JW, Ross J JR, BRAUNWALD E: Effects of intra-aortic balloon counterpulsation on the severity of myocardial ischemic injury following acute coronary occlusion. Circulation 45: 1150, 1972 SUGC WL, MARTIN LF, WEBB WR, ECKER RR: Influence of counterpulsation on right and left coronary blood flow following ligation of the left circumflex coronary artery. J Thorac Cardiovasc Surg 59: 345, 1970 RENEMAN RS, JAGENEAU AHM, SCHAPER WK, BROUWER FAS, VAN GERVEN W: Influence of counterpulsation on collateral circulation after acute occlusion of the left anterior descending coronary artery in dogs. Cardiovasc Res 6: 45, 1972 SHAW J, TAYLOR DR, PITT B: Effects of intra-aortic balloon counterpulsation on regional coronary blood flow in experimental myocardial infarction. Am J Cardiol 34: 552, 1974 HARRIS AS: Delayed development of ventricular ectopic rhythms following experimental coronary occlusion. Circulation 1: 1318, 1950 HOLLANDER W, MADOFF IM, CHOBANIAN AV: Local myocardial blood flow as indicated by the disappearance of Na'31 from the heart muscle: Studies at rest, during exercise and following nitrite administration. J Pharmacol Exp Ther 139: 53, 1963
15. BRANDI G, FAM WM, MCGREGOR M: Measurement of coronary flow in local areas of myocardium using Xenon'33. J Appl Physiol 24: 446, 1968 16. HooD WB JR, COVELLI VH, ABELMANN WH, NORMAN JC: Persistence of contractile behavior in acutely ischemic myocardium. Cardiovasc Res 3: 249, 1969 17. JENNINGS RB, HERDSON PB, SOMMERS HM: Structural and functional abnormalities in mitochondria isolated from ischemic dog myocardium. Lab Invest 20: 548, 1969 18. JENNINGS RB, SOMMERS HM, HERDSON PB, KALTENBACH JP: Ischemic injury of myocardium. Ann N Y Acad Sci 156: 61, 1969 19. JENNINGS RB: Early phase of myocardial ischemic injury and infarction. Am J Cardiol 24: 753, 1969 20. MAROKO PR, KJEKSHUS JK, SOBEL BE, WATANABE T, COVELL JW, Ross J JR, BRAUNWALD E: Factors influencing infarct size following experimental coronary artery occlusions. Circulation 43: 67, 1971 21. MUNDTH ED, YIRCHAK PM, BUCKLEY MJ, LEINBACH RC, KANTROWITZ AR, AUSTEN WC: Circulatory assistance and emergency direct coronary surgery for shock complicating acute myocardial infarction. N Engl J Med 283: 1382, 1970 22. GINKS WR, SYBERS HD, MAROKO PR, COVELL JW, SOBEL BE, Ross J JR: Coronary artery reperfusion. II. Reduction of myocardial infarct size at one week after the coronary occlusion. J Clin Invest 51: 2717, 1972 23. BRESNAHAN GF, ROBERTS R, SHELL WE, Ross J JR, SOBEL BE: Deleterious effects due to hemorrhage after myocardial reperfusion. Am J Cardiol 33: 82, 1974 24. LEAF A, FLORES J, DIBONA D: Regulation of cell volume and renal injury. Clin Sci 42: 25p, 1972 25. BROWN BG, GOLDFARB D, TOPAZ SR, GOTT VL: Diastolic augmentation by intra-aortic balloon: Circulatory hemodynamics and treatment of severe, acute left ventricular failure in dogs. J Thorac Cardiovasc Surg 53: 789, 1967 26. HOOD WB JR, JOISON J, KUMAR R, NORMAN JC, TYBERG JV, URSCHEL CW: Experimental myocardial infarction. VIII. Effects of intra-aortic balloon pump counterpulsation on cardiac performance in intact conscious dogs with left ventricular failure due to coronary insufficiency. Cardiovasc Res 5: 103, 1971 27. SALISBURY PF, CRoss CE, OBLATH RW, RIEBEN PA: Local circulation in heart muscle studied with Na24 clearance method. J Appl Physiol 17: 475, 1962
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Nutrient myocardial blood flow in experimental myocardial ischemia. Effects of intraaortic balloon counterpulsation and coronary reperfusion. V K Saini, W B Hood, Jr, H B Hechtman and R L Berger Circulation. 1975;52:1086-1090 doi: 10.1161/01.CIR.52.6.1086 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1975 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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AND
ROBERT L. BERGER, M.D.
SUMMARY This experimental study was designed to evaluate the effect of intraaortic balloon pumping (IABP) upon nutrient myocardial blood flow (NMBF) following acute myocardial ischemia in dogs, but also to determine whether IABP improves NMBF following revascularization. Localized myocardial ischemia was produced by ligation of one or two small branches of the circumflex coronary artery combined with a three hour snare occlusion of the left anterior descending coronary artery distal to the first septal branch. NMBF was measured by NaIl31 washout at three points corresponding to the peripheral, intermediate, and central zones of the infarct. Occlusion of the coronary arteries reduced NMBF. Release of occlusion after three hours, or the equivalent of coronary artery revascularization, increased NMBF but did not restore it to control levels. The increase in flow was more marked in the peripheral zones of ischemia. IABP increased NMBF significantly both during and after release of occlusion. The effect was sustained after cessation of IABP only when the latter was maintained during the period of reperfusion. The results indicate that NMBF, defined by washout of a locally injected tracer, was improved by both IABP and reperfusion. The beneficial effect was maximal when the two techniques were combined.
EMERGENCY AORTOCORONARY BYPASS revascularization has been employed in patients with acute myocardial ischemia and infarction in an attempt to reperfuse the ischemic myocardium and to permit recovery of left ventricular function.,
we measured the effects of both IABP and revascularization, separately and in combination, upon nutrient myocardial blood flow (NMBF) in an experimental canine ischemic preparation. It was shown that NMBF, defined by washout of a locally injected tracer, was improved by both interventions, and was maximal when they were used
Another method of reclaiming ischemic myocardium is the use of intraaortic balloon pumping (IABP), which decreases left ventricular workload and increases coronary perfusion pressure. This technique has been employed with some success in treating patients with cardiogenic shock due to acute myocardial infarction.5 It has been suggested from experimental studies that IABP promotes the development of functional coronary collaterals6 and may reduce the size of infarcts in experimental animals.7-9 However, others were not able to reproduce these
simultaneously. Methods Studies were carried out in 22 mongrel dogs with a mean weight of 30.9 ± 2.1 (SEM) kg. Animals were anesthetized with 25 mg/kg of sodium pentobarbital. Respiration was maintained after endotracheal intubation by a Harvard respirator with a 40% oxygen mixture. The heart was exposed through a left thoracotomy. A grossly visible confluent area of acute myocardial ischemia was produced by ligation of one to two small peripheral branches of the circumflex coronary artery, and then temporary occlusion of the left anterior descending coronary artery (LAD) distal to the first perforator branch with a removable snare. This technique permitted a staged temporary occlusion13 and was designed to simulate clinical coronary occlusion followed by revascularization. A schematic drawing of the experimental preparation is shown in figure 1. Monitoring of aortic and left atrial pressures and of cardiac output was carried out. Pressures were obtained using catheters connected to Statham P23Db transducers, and were recorded on a Hewlett-Packard multichannel recorder. The zero level for pressure measurements was set at the mid-chest. Serial cardiac output determinations were made using the indicator dilution technique, by injecting in-
salutary results.0102 In an effort to clarify further the role of these two forms of therapy in ameliorating myocardial ischemia, From the Department of Cardiothoracie Surgery and the Medical Service, Boston City Hospital and Boston University Medical Center, Boston, Massachusetts. Supported by the Norwich Thoracic Research Fund, USPHS Grants HL 71-2498, HL 14646, and HE 07299, and American Heart Association Grant 74-1013. Address for reprints: Robert L. Berger, M. D., University Hospital, 75 East Newton Street, Boston, Massachusetts 02118. Received May 27, 1975; revision accepted for publication July 3, 1975.
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through the femoral artery and positioned in the descending thoracic aorta distal to the left subelavian artery. The animals were divided into three groups: Group I (control nine dogs). Myocardial ischemia was produced as described above and the LAD snare was -
Figure 1 Diagrammatic representation of the experimental model of (hatched area). Nutritional myocardial blood by NaI'31 injection at three points (A, B, C), corresponding to the peripheral, intermediate and central zones of ischemia. L.A.D. = left anterior descending coronary artery.
coronary ischemia flow was measured
docyanine green dye into the right atrium and sampling from the aorta. Nutrient myocardial blood flow was measured with the NaIl3` washout technique" by injecting 10 gCi of the isotope 3 mm into the myocardium in a volume of 0.1 cc with a 25 gauge needle (fig. 1). Radioactivity over the site of the injection was measured with a Picker Nuclear Omniprobe Model 12830-A through a Baird Atomic analog rate meter counter and recorded on a Gilson direct writing linear recorder. The difference between extrapolated background and the points along the washout curve were replotted on semilogarithmic paper. NMBF was calculated in ml/min/100 gm myocardium.`5 Sequential injections and measurements of NMBF were carried out at three preselected sites, A, B and C, which corresponded to peripheral, intermediate and central portions of the ischemic zone (fig. 1). An AVCO* helium-driven pumping system utilizing a three segmented balloon mounted on a 12 or 14F catheter was employed in these studies. The circuitry is designed to permit triggering of inflation and deflation from the electrocardiogram. Balloons of either 20 or 30 cc capacity, depending upon the size of the animal, were inserted Everett Research Laboratory, Everett, Mass.
released after three hours of occlusion. This model is analogous to acute coronary occlusion and early myocardial revascularization. NMBF was measured prior to occlusion, ten minutes after coronary occlusion, just prior to release of the LAD snare and ten minutes after restoration of flow through the coronary artery (fig. 2). Group II (six dogs). Coronary artery occlusion was carried out as in the controls. IABP was initiated ten minutes after the application of the LAD snare (following NMBF measurement) and was discontinued ten minutes prior to reflow to LAD. This sequence is analogous to the clinical situation in which IABP is used in the preoperative phase but only prior to coronary revascularization. NMBF was measured, as in the controls, before and ten minutes after the coronary occlusion, ten minutes prior to and ten minutes following cessation of IABP and finally ten minutes after release of the LAD occlusion (fig. 2). Group III (seven dogs). This group was treated similarly to group II with the exception that IABP support was continued after the release of the LAD snare. In the clinical setting this sequence is analogous to pre and postrevascularization circulatory support. NMBF was measured before and ten minutes after coronary occlusion, after three hours of IABP, ten minutes following release of occlusion with IABP still in effect, and finally ten minutes after stopping IABP (fig. 2). Statistical comparisons were carried out using Student's ttest, using paired data when appropriate. Results
Occlusion of the left anterior descending coronary resulted in appearance of a noncontracting cyanotic area of ischemia on the anterior surface of the left ventricle. However, only modest changes in hemodynamic measurements were noted after coronary occlusion; severe cardiac failure or cardiogenic artery
[3 Coronary M IABP 131I
Occlusion
Injection
GROUP I
_..
..........................
GROUP
ll
I
GROUP 0
4
2
3
HOURS
Figure 2 Experimental protocol showing timing of coronary occlusion and reflow for groups I-II1, and timing of IABP in groups II and III.
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absent. Cardiac output fell from 103 ± 5 7 ml/min/kg (P < 0.01), and left atrial mean pressure rose from 8.4 ± 0.5 to 11.3 ± 0.6 mm Hg (P < 0.001), while aortic mean pressure did not change significantly (121 ± 4 mm Hg before and 115 ± 5 mm Hg after occlusion). With institution of IABP, evidence of diastolic augmentation was documented in each animal in groups II and III from the aortic pressure tracings. Measurements of NMBF in the three groups of animals are shown in table 1. In group I (control) animals, NMBF was markedly depressed at all three points of measurement following coronary occlusion.
of IABP. The response was similar to that seen in group II animals, which, up to this point in time, had been treated in identical fashion to group III animals (table 1). Release of the coronary occlusion, with continuation of IABP, resulted in a marked rise in NMBF, especially in the more peripheral zones of the ischemic area (points A and B). After cessation of IABP, NMBF again declined, but the values were, in this case, significantly higher than in control animals during reflow.
The values remained at this low level during the three hours of occlusion, but then rose significantly following release of the snare. However, the flow values were still reduced below the control state. Point C in the center of the ischemic zone showed the lowest flow values, while at points A and B, or the more peripheral portions of the infarct, the flows were higher. In group II animals coronary occlusion likewise produced a marked fall in NMBF in all three zones of ischemia (table 1). However, after three hours of IABP, a significant increase in NMBF occurred at all three points in comparison to control animals. When IABP was discontinued with the coronary occlusion still in effect a second fall in NMBF was observed. When the LAD snare was released NMBF rose again, but the values were not significantly different from those observed with reflow in the control animals. In group III animals NMBF fell following application of the LAD snare, but rose again after three hours
injury and reduced contractile performance`6 of the
shock to 87
were
±
Occlusion of zone
a
Discussion coronary artery results in ischemic
of myocardium supplied by the stenosed vessel.
In the early phases of ischemia these functional
changes are readily reversible with reperfusion.'6 Electron microscopic and histochemical studies reveal that, for a period up to 20 minutes after coronary occlusion, irreversible injury does not take place.'7-19
Furthermore, even when ischemia is prolonged and a central zone of irreversible ischemic injury is present, the margins of the infarct may contain viable myocardium. Data have been obtained suggesting that a number of metabolic and hemodynamic interventions,20 among them intraaortic balloon pumping,7-9
reduce ischemic damage. The question of how long myocardium may remain ischemic and yet be restored to normal function following revascularization has not yet been fully answered. From limited experience with emergency revascularization procedures in patients, there is may
Table 1 Nutrient Myocardial Blood Flow (ml/min/100 gm myocardium) Control Group
I
Point
A B C
II
III
A B C
A B C
preocclusion
72.3 73.7 69.7
77.8 69.5 64.3 90.9 91.3 91.7
8.4§ 7.4 7.3
-
-
-
8.8 8.4 6.8 53.3 5.3 9.6
Occlusion (10 min)
Occlusion (3 hr)
15.7 * 2.2t 14.8 i 2.4 11.1 i 2.0
1a.0 3 2.4t 1.3* 9.9 7.2 i 1.4 Occlusion plus IABP
12.6 i 3.1 11.2 2.2 12.4 1.8
10.8 11.6 10.4
-
-
1.4 2.7 2.5
335.0
8.9*1 3.7*1 - 4.0*1 Occlusion plus IABP
23.3 24.8 24.1 18.2 16.5
-
-
-
-
Reflow
38.3 i 3.9*t 39.7 4-3*t 24.7 4.7*
Occlusion minus IABP 19.2 - 4.8* 16.2 - 3.8* 13.6 - 3.4
2.1*1l
2.4*1 2.71
43.7 42.3 32.2
Reflow plus IABP 73.1 - 8.1*1t 70.4 - 8.3*1 54.6 - 11.0*t
9.0*
i 8.1* 8.0
i 7.0*t1 7.7*1 49.7 i 9.4*1 68.7
59.9
All occlusion (10 min) values differ significanitly (P < 0.03) from control preocclusion. Intragroup comparisons (paired differences): *P < 0.03, compared to postocclusioii (10 niin). tP < 0.05, compared to point C. Intergroup comparisons (unpaired differences): JP < 0.05, compared to group I.
§Expressed
as mean- SEM.
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Volume
52,
December 1975
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IABP AND REPERFUSION IN CARDIAC ISCHEMIA
evidence that restoration of function may be possible after hours3 4 or even days of ischemia.21 Most experimental studies, however, indicate that much briefer periods of reduced blood flow are critical. In the normal canine ventricle, temporary coronary occlusion lasting from forty-five minutes'9 to three hours22 causes permanent myocardial damage. Furthermore, reperfusion after five hours of ischemia produces variable results, with some animals showing reduction of ultimate infarct size and others hemorrhage into the ischemic zone with infarct extension.23 The present study provides additional evidence that coronary occlusion for three hours produces lasting deleterious effects upon the coronary circulation in that reperfusion provides only partial benefit and does not restore NMBF to preocclusion levels. The mechanism for these findings is uncertain, but may relate to tissue edema or capillary endothelial swelling, analogous to the no-reflow phenomenon in other tissues.24 Evidence available to date suggests that IABP is effective in reducing infarct size7`9 and in lowering mortality2` in experimental coronary occlusion. This may be due in part to reduction of myocardial oxygen demands by lowering afterload, and also, in unanesthetized animals, cardiac rate.26 In addition, some authors have suggested that coronary collateral flow may be improved as a result of augmentation of diastolic pressure.ff 7 These conclusions were, however, based upon indirect methods of assessing collateralization, including postmortem coronary angiograms5 and detection of increased coronary blood flow in unoccluded coronary arteries supplying normal myocardium adjacent to an infarct.7 Attempts to measure changes in NMBF induced by IABP have thus far failed to demonstrate conclusively that collateral flow is increased by this intervention."' 12 In the study performed by Reneman et al.,1 washout of indicator injected into the center of the ischemic zone was not increased significantly by a three-hour period of IABP. In the present study, a modest increase in NMBF was observed in the infarct center with IABP. Changes resulting from IABP were, however, more marked in the peripheral and intermediate zones of ischemia, especially in the postreperfusion period. In the study performed by Shaw et al.,12 a brief period of IABP (30 min) did not significantly improve flow as measured by microsphere techniques in either the center or border zones of ischemic myocardium, although the reduced ratio of endocardial to epicardial blood flow in the ischemic border zone was significantly increased by IABP. The disparity between the latter study and the present one might be explained by differences in the duration of IABP.
In the present study NMBF was assayed by the injection of sodium radioiodide directly into the myocardium. The rate of disappearance of this indicator has been shown to reflect local myocardial blood flow."' Other investigators'5' 27 have used this technique with various indicators to study the local circulation in the myocardium, and although the method may not be precisely quantitative in terms of providing absolute blood flow values, it is possible to detect directional changes of flow.15 Three points of measurement distributed from the center to the margins of the infarct were selected in order to evaluate changes in the NMBF in different zones of the infarct. In control animals release of occlusion after three hours of ischemia, or the equivalent of coronary artery revascularization, increased NMBF but did not restore it to control. In animals treated with IABP, the increase in NMBF was most marked in the intermediate and peripheral zones of the infarct. However, the increment in blood flow produced by IABP which was terminated prior to reflow was limited to the duration of the assist and did not influence the levels of NMBF after reperfusion. When IABP was maintained into the postreperfusion period, high values of NMBF were observed, and, when IABP was finally withdrawn, the increased flow persisted at higher levels than those observed in control studies. Though extrapolation of these animal experiments to the clinical setting in patients with myocardial infarction must be done with caution, these data may have clinical implications. It may be that intraaortic balloon pumping should be carried out in patients for prolonged periods of time following coronary revascularization procedures to permit maximal effects upon nutrient myocardial blood flow and presumably also upon recovery of potentially viable
myocardium. Acknowledgment We should like to express our appreciation to J. Patel, M.D., R. Diorio, B. Ugarte, M. Cassidy, R. Rosen and W. Wright for their asssistance in carrying out these studies.
References 1. SCANLON PJ, NEMICKAS R, TOBIN JR JR, ANDERSON W, MONTOYA A, PIFARRE R: Myocardial revascularization during acute phase of myocardial infarction. JAMA 218: 207, 1971 2. MUNDTH ED, BUCKLEY MJ, DAGGETT WM, SANDERS CA, AUSTEN WG: Surgery for complications of acute myocardial infarction. Circulation 45: 1279, 1972 3. CHATTERJEE K, SWAN HJ, PARMLEY WW, SUSTAITA H, MARCUS H, MATLOFF J: Depression of left ventricular function due to acute myocardial ischemia and its reversal following aortocoronary saphenous-vein-bypass. N Engl J Med 286: 1117, 1972
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4. CHEANVECHAI C, EFFLER DB, Loop FD, GROVES LK, SHELDON WC, RAZARI M, SONES M: Emergency myocardial revascularization. Am J Cardiol 32: 901, 1973 5. SCHEIDT S, WILNER G, MUELLER H, SUMMERS D, LESCH M, WOLFF G, KRAKAUER J, RUBENFIRE M, FLEMING P, NooN G,
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OLDHAM N, KILLIP T, KANTROWITZ A: Intra-aortic balloon counterpulsation in cardiogenic shock. Report of a cooperative clinical trial. N Engl J Med 288: 979, 1973 JACOBEY JA, TAYLOR WJ, SMITH GT, GORLIN R, HARKEN DE: A new therapeutic approach to acute coronary occlusion. II. Opening dormant coronary collateral channels by counterpulsation. Am J Cardiol 11: 218, 1963 RoSENSWuEIc J, CHATTERJEE S: Mechanical augmentation of coronary circulation in the ischemic heart: Angiographic and hemodynamic correlation with prolonged survival. J Thorac Cardiovasc Surg 54: 839, 1968 GOLDFARB D, FRIESINGER GC, CONTI CR, BROWN BG, GOTT VL: Preservation of myocardial viability by diastolic augmentation after ligation of the coronary artery in dogs. Surgery 63: 320, 1968 MAROKO PR, BERNSTEIN EF, LIBBY P, DELARIA GA, COVELL JW, Ross J JR, BRAUNWALD E: Effects of intra-aortic balloon counterpulsation on the severity of myocardial ischemic injury following acute coronary occlusion. Circulation 45: 1150, 1972 SUGC WL, MARTIN LF, WEBB WR, ECKER RR: Influence of counterpulsation on right and left coronary blood flow following ligation of the left circumflex coronary artery. J Thorac Cardiovasc Surg 59: 345, 1970 RENEMAN RS, JAGENEAU AHM, SCHAPER WK, BROUWER FAS, VAN GERVEN W: Influence of counterpulsation on collateral circulation after acute occlusion of the left anterior descending coronary artery in dogs. Cardiovasc Res 6: 45, 1972 SHAW J, TAYLOR DR, PITT B: Effects of intra-aortic balloon counterpulsation on regional coronary blood flow in experimental myocardial infarction. Am J Cardiol 34: 552, 1974 HARRIS AS: Delayed development of ventricular ectopic rhythms following experimental coronary occlusion. Circulation 1: 1318, 1950 HOLLANDER W, MADOFF IM, CHOBANIAN AV: Local myocardial blood flow as indicated by the disappearance of Na'31 from the heart muscle: Studies at rest, during exercise and following nitrite administration. J Pharmacol Exp Ther 139: 53, 1963
15. BRANDI G, FAM WM, MCGREGOR M: Measurement of coronary flow in local areas of myocardium using Xenon'33. J Appl Physiol 24: 446, 1968 16. HooD WB JR, COVELLI VH, ABELMANN WH, NORMAN JC: Persistence of contractile behavior in acutely ischemic myocardium. Cardiovasc Res 3: 249, 1969 17. JENNINGS RB, HERDSON PB, SOMMERS HM: Structural and functional abnormalities in mitochondria isolated from ischemic dog myocardium. Lab Invest 20: 548, 1969 18. JENNINGS RB, SOMMERS HM, HERDSON PB, KALTENBACH JP: Ischemic injury of myocardium. Ann N Y Acad Sci 156: 61, 1969 19. JENNINGS RB: Early phase of myocardial ischemic injury and infarction. Am J Cardiol 24: 753, 1969 20. MAROKO PR, KJEKSHUS JK, SOBEL BE, WATANABE T, COVELL JW, Ross J JR, BRAUNWALD E: Factors influencing infarct size following experimental coronary artery occlusions. Circulation 43: 67, 1971 21. MUNDTH ED, YIRCHAK PM, BUCKLEY MJ, LEINBACH RC, KANTROWITZ AR, AUSTEN WC: Circulatory assistance and emergency direct coronary surgery for shock complicating acute myocardial infarction. N Engl J Med 283: 1382, 1970 22. GINKS WR, SYBERS HD, MAROKO PR, COVELL JW, SOBEL BE, Ross J JR: Coronary artery reperfusion. II. Reduction of myocardial infarct size at one week after the coronary occlusion. J Clin Invest 51: 2717, 1972 23. BRESNAHAN GF, ROBERTS R, SHELL WE, Ross J JR, SOBEL BE: Deleterious effects due to hemorrhage after myocardial reperfusion. Am J Cardiol 33: 82, 1974 24. LEAF A, FLORES J, DIBONA D: Regulation of cell volume and renal injury. Clin Sci 42: 25p, 1972 25. BROWN BG, GOLDFARB D, TOPAZ SR, GOTT VL: Diastolic augmentation by intra-aortic balloon: Circulatory hemodynamics and treatment of severe, acute left ventricular failure in dogs. J Thorac Cardiovasc Surg 53: 789, 1967 26. HOOD WB JR, JOISON J, KUMAR R, NORMAN JC, TYBERG JV, URSCHEL CW: Experimental myocardial infarction. VIII. Effects of intra-aortic balloon pump counterpulsation on cardiac performance in intact conscious dogs with left ventricular failure due to coronary insufficiency. Cardiovasc Res 5: 103, 1971 27. SALISBURY PF, CRoss CE, OBLATH RW, RIEBEN PA: Local circulation in heart muscle studied with Na24 clearance method. J Appl Physiol 17: 475, 1962
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Nutrient myocardial blood flow in experimental myocardial ischemia. Effects of intraaortic balloon counterpulsation and coronary reperfusion. V K Saini, W B Hood, Jr, H B Hechtman and R L Berger Circulation. 1975;52:1086-1090 doi: 10.1161/01.CIR.52.6.1086 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1975 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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