Noncoronary Collateral Myocardial Blood Flow John Brazier, M.D., Christof Hottenrott, M.D., a n d Gerald Buckberg, M.D.
ABSTRACT This study shows that noncoronary collateral flow occurs in normal hearts after chronic coronary occlusion and with left ventricular hypertrophy in variable amounts (0.2 to 16 ml/lOO gmlmin). Luminal-left ventricular flow is negligible in the working heart. Nonluminal noncoronary collateral flow is greatest when the heart is arrested by aortic cross-clamping, falls significantly when perfusion pressure is lowered to 50 mm Hg, and increases slightly when blood viscosity is reduced (hemodilution).Our findings indicate that the heart which is arrested by aortic cross-clamping may not be anoxic.
C
ardiac arrest is induced when coronary flow is interrupted by cross-clamping the aorta; a quiet, dry operative field is thus obtained for intracardiac operations. Occasionally, however, the heart does not stop beating or continues to fibrillate despite aortic cross-clamping. These observations suggest that the myocardium may not be anoxic when coronary flow is interrupted and that it receives nourishment from another source. Evidence for extracoronary collateral flow is provided by an occasional outpouring of arterial blood from the coronary ostia when the aorta is opened during valve replacement or from the coronary artery when it is incised during revascularization. This flow occurs in the arrested heart despite adequate venting of the left ventricle and decompression of the coronary sinus to prevent retrograde flow. Other evidence suggestive of extracoronary collateral flow is provided by the excellent ventricular function sometimes seen in patients with complete occlusion of the three major coronary vessels. While the source of the collateral flow is uncertain, some believe it originates from the ventricular lumen and proceeds directly into the myocardium [17, 18, 231. This study was designed to determine if noncoronary collateral flow (1) occurs, (2) is greater in hearts that are ischemic or hypertrophied, (3) can be affected by changes in perfusion pressure of blood viscosity during aortic crossclamping, and (4) originates from the ventricular lumen.
Methods Studies were performed in 22 tnongrel dogs weighing 15 to 25 kg and separated into three experimental groups. From the Division of Thoracic Surgery, UCLA School of Medicine, L a s .\ngeles, Calif. Accepted for publication Nov. 5 , 1974. Supported by grants-in-aid from the U.S. Public Health Service. Blalock Found;ition. M'ilbur \ l a \ Foundation, Frank W. Clark, Jr., Charities, and Beaumont Foundation. Address reprint requests to Dr. Buckberg, Division of Thor;iric Surgery. L1CL.A School o f Medicine, Los Angeles, Calif. 90024.
426
T H E ANNALS OF THOKACIC SUKGEKY
Noncoronary Collateral Myocardial Blood Flow Group I (acute). This group comprised 12 dogs in which no prior operation had been performed. Group I1 (chronic coronary occlusion).Six to eight months prior to the study, 12 dogs underwent left thoracotomy (under fluothane anesthesia) and an ameroid constrictor was placed around the proximal circumflex coronary artery; the 8 surviving animals were included in the present experiments. Group I11 (left ventricular hypertrophy). Five to seven months before this study, 6 dogs underwent median sternotomy (under fluothane anesthesia) and the supravalvular aorta was constricted (60 to 90 mm gradient) to produce left ventricular hypertrophy [ 131; 2 surviving dogs were studied. EXPERIMENTAL PREPARATION
Anesthesia was induced with morphine, 3 mg per kilogram of body weight intramuscularly, and chloralose, 15 mg per kilogram intravenously. Respiration was maintained with an endotracheal tube and positive-pressure respirator. Following bilateral thoracotomy, polyethylene catheters were placed into the ascending aorta, femoral artery, left atrium, and coronary sinus. Pressures were recorded with a Statham P23DB pressure transducer on a Hewlett-Packard multichannel recorder. Cardiopulmonary bypass was instituted by diverting superior and inferior vena caval blood into a bubble oxygenator primed with whole blood and returning it into the femoral artery under normothermic conditions. The left ventricle was vented with a catheter placed through the left atrial appendage, and the right ventricle with a catheter placed directly into the outflow tract. Ventricular pressure was recorded continually to assure adequacy of venting. Regional myocardial blood flow was measured by determining the myocardial distribution of 8- to 10-p microspheres labeled with cerium 141, strontium 85, and scandium 46. A reference sample was collected from a peripheral artery during each microsphere injection. After the procedure the dogs were killed with magnesium sulfate; the hearts were then removed and separated into left and right atria, right ventricle, intraventricular septum, and left ventricular free wall. The left ventricular free wall was further divided into two parts: the region perfused by the left anterior descending coronary artery (apex), and the region perfused by the left circumflex coronary artery (base).The left ventricle sections were then further subdivided into subendocardial, subepicardial, and midmyocardial layers of approximately equal thickness. Total and regional flows were calculated from the equation:
where Fl, is flow to the heart, CI,is counts in the heart, F, is flow in the reference saniple (iiil/min), antl C , .is counts in the reference sample [5, 201. Flows were reported o n l y when there was a ininiinum o f 400 microspheres in both the i.efei.ence sample antl tissue specimen, since this is the minimum number of sphei.es necessary for accurate flow ineasureinent [4].
VOL. 19, NO. 4, APRIL, 1975
427
BRAZIER, HOTTENROTT, AND BUCKBERG Hemoglobin was measured by the cyanohemoglobin method, pH and PCOZ by the Astrup method, and arterial venous Po2 and oxygen content by the Severinghaus method. The pH was between 7.35 and 7.45 in all studies, and Po2 was maintained above 100 mm Hg. Hematocrit was maintained at 40% by adding blood to the reservoir. When hemodilution was used, hematocrit was reduced to 20% by exchanging reservoir blood for Ringer’s lactate solution. EXPERIMENTAL PROCEDURE
Beating, Working Heart. In all dogs, microsphere injections were made under control conditions with the heart beating and doing external work and prior to institution of cardiopulmonary bypass; mean aortic blood pressure was maintained at 100 mm Hg by either withdrawal or addition of blood. To assess the possible presence of noncoronary collateral blood flow, we studied 4 dogs with chronic coronary occlusion in whom the left ventricle was perfused with non-microsphere-containing blood. The left main coronary artery was dissected and a tape passed around it (above the septa1branch), and the right coronary artery was encircled with a tape close to its aortic origin. Using cardiopulmonary bypass, a femoral vein graft was sewn end-to-side into the left anterior descending coronary artery, and the proximal end was connected to a reservoir containing oxygenated blood. Cardiopulmonary bypass was discontinued and the left main coronary artery occluded with a vascular clamp. Perfusion of the heart was maintained with a roller pump by means of the vein graft from the reservoir of oxygenated blood. Coronary perfusion pressure was recorded from a side-branch of a vein graft and was maintained equal to aortic blood pressure (100 mm Hg). The right coronary artery was occluded so that all coronary myocardial flow was provided by the vein graft. Microspheres were injected into the left atrium while the vein graft was perfused with non-microsphere-containing blood from the reservoir at a perfusion pressure of 100 mm Hg. A reference sample was collected simultaneously from the femoral artery. Arrested Heart. Cardiac arrest was produced by occluding both the aorta and pulmonary artery with a vascular clamp placed through the transverse sinus in 12 dogs in the acute group (Group I) and 10with chronic occlusion (Group 11).After we were certain that both ventricles and the supravalvular aorta were empty (zero pressure), we injected microspheres into the perfusion circuit through the femoral perfusion cannula. A reference sample was collected from the contralatera1 femoral artery. During cardiac arrest, perfusion pressure was lowered from 100 to 50 mm Hg in 3 Group I dogs and the microsphere injection was repeated. In addition, blood viscosity was reduced in 7 Group I1 dogs (those with ameroid constrictors) by diluting the perfusion reservoir with Ringer’s lactate solution until the hematocrit was lowered to 20%. Microsphere injections were made at this lowered hematocrit.
Results
At operation, extensive collateral vessel formation was seen on the surface of the heart in all dogs in which an ameroid constrictor had been placed around the 428
THE ANNALS OF THORACIC SURGERY
Noncoronary Collateral Myocardial Blood Flow Proximal LCA , 7 \ \, < , Ameroid
Arteriogram and drawing ofpostmortem coronary angiogram made after injection of Hypaque into the vein graft. Note ( I ) occlusion of the left circumflex coronary artery (LCA) by the ameroid constrictor, and (2) the intercoronary collaterals from the left anterior descending (LAD) artery to the left circumflex coronary artery. This extensive collateralformation explains the normal distribution of coronaryflow under resting conditions despite total occlusion of the 1eJ circumflex coronary artery.
left circumflex coronary artery. These collaterals originated from the left anterior descending and right coronary arteries. They were demonstrated by postmortem angiograms obtained by injection of Hypaque into the vein graft while the main left coronary arteries were occluded (Figure). T h e posterior papillary muscle was scarred in 2 dogs. Beating, Working Heart. Total left ventricular coronary flow was similar in Group I dogs (85 f 17 ml per 100 gm of tissue per minute), in dogs with chronic circumflex occlusion, Group I1 (108 iz 17 mVlOO g d m i n ) , and in the 2 dogs with left ventricular hypertrophy, Group I11 (83 mV100 gm/min) (Table 1). T h e left and right atria received flows ranging from 15 to 80 m1/100 gmlmin in both Group I and Group I1 dogs. Since the atrial mass is low, the actual mean atrial flow was only 7 ml/min in the beating heart. Equal amounts of left ventricular flow were delivered to the area in the distribution of the left anterior descending coronary artery (apex) and left circumflex coronary artery (base) in all studies. T h e apexlbase flow ratio was 1.07 in Group I dogs and 1.07 in dogs with chronic coronary artery occlusion; a similar ratio was seen in dogs with left ventricular hypertrophy (1.02). Coronary flow was distributed evenly across the myocardial wall of the left ventricular apex and base in all groups (endocardial/epicardial flow ratio: Group I, 1.12; chronic coronary occlusion group, 1.03; and group with left ventricular hypertrophy, 1.10) ( p > 0.5). While nutritive flow to the beating, working left ventricle averaged 102 m1/100 gm/min in dogs with chronic coronary artery obstruction (Group 11), the maximum flow delivered from noncoronary sources was 0.25 ml/100 gm/min when the left coronary artery was perfused with non-microsphere-containing blood at a perfusion pressure of 100 mm H g (Table 2). Only 1 of 4 hearts received more than 400 microspheres despite the presence of more than 7,000 microspheres in the reference sample in each study (collected at 5 ml/min). Flow as low VOL. 19, NO. 4, APRIL, 1975
429
BRAZIER, HOTTENROTT, AND BUCKBERG T.\BLE 1.
RESC'LTS IN BE..ZTING, WORKING HEART UNDER NORMAL. PERFUSION
(;t~ollp I - acute
(S = 3)
- chiwnic circuiiifles occl ttsion ( S = 6) 1 1 1 - ventriciil:ir 11ypert t.O),Il! ( S = 2)
11
1.V Flow (nil/ 100 gtii/inin)
1.v .Apex/Base Flow Ratio
8 5 f 17
1 . 0 7 & 0 . 0 9 1.12kO.17
1.6fO.3
42
1.07 ? 0.03
1.03 f 0.09
1.3 & 0 . 1
75 f 27'
1.02
0.97
...
...
108 f 17 79.87
' p < 0.0 1.
1.V
=
left venti.icitl;ir:
E t i t l o = eiitloc;irdi;il:
LV l,eft/Right LA Flow Entlo/Epi Ven tricu lar (mu100 Flow Ratio Flow Ratio gm/min)
Epi = epicartliiil: I..\
=
f
10
left atrial.
as 0.2 mllmin can be measured accuratelywhen the reference sample contains this many spheres 141. Consequently, noncoronary collateral flow in 3 working hearts was too low to measure accurately. When sufficient microspheres were present, left ventricular (LV) flow was distributed evenly across the myocardium (endocardial/epicardial ratio = 1.06)and between the apex and base (apexlbase = 1.03) but totalled only 0.25 mlll00 gmlmin. Arrested Heart. The values for total and regional noncoronary collateral flow are shown in Table 3. Sufficient microspheres were present in the myocardium to calculate noncoronary collateral LV flow in 5 of 12 Group I dogs, 4 of 8 Group I1 dogs, and both Group I11dogs. In Group I dogs left ventricular noncoronary collateral flow was 2 and 13 mllmin, respectively, in 2 dogs and less than 0.4 m1/100 gmlmin in the 3 other dogs in which sufficient microspheres were present to measure flow accurately. Left ventricular flow was 0.6,2.0,5.0, and 5.6 m1/100 gm/min, respectively, in the 4 dogs with chronic left circumflex coronary occlusion (Group 11). The highest total left ventricular flow originating from noncoronary collateral sources occurred in the 2 dogs with left ventricular hypertrophy (12 and 16 m1/100 gmlmin, respectively). Atrial arrest was always delayed when compared with ventricular arrest. In some dogs the atria continued to beat for up to 30 minutes after the ventricle stopped contracting. The left and right atria received an average of 4 m1/100 gmlmin (total flow 0.2 mllmin) in Group I dogs and 12 m1/100 gmlmin (total flow 0.7 mllmin) in dogs with circumflex occlusion, Group I1 (p > 0.01). Left and right atrial flows could be measured and were comparable in all studies. During arrest the left ventricle received twice as much noncoronary collateral flow as the right ventricle (left ventriclelright ventricle flow ratio = 2.6 during arrest and 1.5 in the beating heart with normal coronary perfusion). This noncoronary collateral flow, however, was relatively evenly distributed between the left ventricular apex and base (left anterior descending and circumflex coronary artery distribution) in all studies. There was therefore no increase in collateral flow to the left ventricular base which had its nutrient channel occluded by the ameroid constrictor (see Table 3). The flow delivered to both the apical and basal 430
THE ANNALS OF THORACIC SURGERY
Noncoronary Collateral Myocardial Blood Flow
portions of the heart was also evenly distributed between the inner and outer shells of the ventricle. Lowering perfusion pressure from 100 to 50 mm Hg resulted in almost total cessation of all noncoronary collateral flow to the left ventricle in each of 3 Group I dogs in which flow had been present at higher perfusion pressure (0.07 m1/100 gmlmin). Although reducing the hematocrit to 20%(perfusion pressure 100 mm Hg) resulted in an increase in noncoronary collateral flow in 4 of 7 dogs with chronic coronary occlusion, the flow increment averaged only 1 ml/min and the flow distribution did not change (Table 4).With hemodilution, coronary flow increased less than oxygen-carrying capacity fell.
Comment The possible occurrence of noncoronary collateral myocardial blood flow was noted first by Thebesius in 1708 when he described openings in the inner walls of the atria and ventricles. Although the potential for collateral flow from the left ventricular lumen to its inner shell is possible anatomically, physiological considerations suggest that the left ventricular cavity is an unlikely source of nutrient blood supply to the subendocardium [ 1,2]. Intramyocardial compressive forces in the subendocardium are equal to or exceed intracavitary pressure during systole
VOL. 19, NO. 4, APRIL, 1975
43 1
BRAZIER, HOTTENROTT, AND BUCKBERG and would therefore retard flow from the lumen to the wall during myocardial contraction. During diastole, coronary blood pressure exceeds the cavitary pressure so that the gradient for flow would be from the coronary arteries to the cavity rather than in the reverse direction. If these collateral channels were important, we would expect subendocardium to be the part of the heart least vulnerable to ischemic injury, rather than the area that is injured most when coronary blood supply is inadequate [ 1 1, 2 11. Attempts to quantitate noncoronary collateral myocardial flow with diffusible indicators are difficult to assess since penetration of the myocardium by means of perfusion cannot easily be differentiated from penetration by diffusion. Studies by Moir and DeBra [19] comparing the movement of radioiodinated albumin (l 3 I I ) particulate indicators with rubidium 86 diffusible indicators show that diffusion rather than movement through vascular channels is the way that rubidium enters the endomyocardium. Fixler and associates 171 recently studied noncoronary collateral flow using 8- to 10-/.tradioactive microspheres and found that the maximum noncoronary flow, even with experimental coronary occlusion, is only 0.15 m1/100 gmlmin. We found a similarly minute, noncoronary collateral flow in our study in which the working left ventricle was perfused with nonmicrosphere-containing blood (< 0.25 m1/100 gmlmin in each of 4 dogs). The microsphere method allows for accurate flow measurement if a minimum of 400 spheres is present in both the region of interest and the reference sample. In each of our studies the reference sample contained more than 7,000 microspheres (collected at 5 ml/min). Consequently we could expect to accurately measure flows as low as 0.2 mllmin. The absence of microspheres in the beating, working heart when the coronary arteries were perfused with nonmicrosphere-containing blood is therefore due to the absence of flow from noncoronary sources rather than a limitation of the microsphere method. Conclusions could not be drawn about the precise origin of this slight amount of extracoronary collateral flow in the working heart because sources of potential TABLE 4. EFFECTS OF VARYING PERFUSION PRESSURE AND VISCOSITY ON NONCORONARY COLLATERAL FLOW
Aorta Cross-Clamped Group I - acute Perfusion pressure = 100 mm Hg (N = 5) Perfusion pressure = 50 mm Hg (N = 3) Group I1 - chronic circumflex occlusion Hematocrit = 40% (N = 4) Hematocrit = 20% (N = 4)
LV Flow (mV100 gm/min)
LefdRight LV LV ApedBase Endo/Epi Ventricular Flow Ratio Flow Ratio Flow Ratio
3.32 5.6
1.062 0.69 1.07k 0.56
2.2k 0.5
0.0720.03*
1.1720.49 1.14k0.89
1.7+ 1.2
3.3k 2.4 4.3 2 3.5*
0.96+ 0.71 0.862 0.62 1.32 2 1.00 0.85 2 0.37
2.62 0.5 1.8 +- 0.6
*p < 0.01.
LV = left ventricular; Endo = endocardial; Epi = epicardial.
432
THE ANNALS OF THORACIC SURGERY
Noncoronary Collateral Myocardial Blood Flow noncoronary collateral flow other than the ventricular lumen are known to occur. Several studies have shown that extracoronary collateral vessels arising from mediastinal, pericardial, and bronchial collateral channels enter the heart through pericardial reflections surrounding pulmonary and systemic veins as well as from vasa vasorum along the major vessels leading to and from the myocardium [3, 12, 14, 15, 221. In designing the present study, we simulated clinical conditions in which noncoronary collateral flow is encountered (i.e., chronic myocardial ischemia o r left ventricular hypertrophy), made comparisons with normal hearts, and separated luminal-mural flow from other extracoronary collateral sources. In all studies, flow delivered from noncoronary collaterals was greatest (up to 16 ml/ 100 gm/min) when the heart was arrested by aortic cross-clamping. This observation supports the conclusion that ventricular-luminal flow is not a significant source of extracoronary collateral blood supply; the ventricles could not provide nutrient flow since their cavities were emptied, the heart generated no pressure, and ebb and flow could not occur due to cardiac arrest. We found that the highest proportion of noncoronary collateral flow was always delivered to the atria, which receive up to 30% of their resting flow (beating, working heart) from noncoronary sources during aortic cross-clamping. While total atrial flow was only 0.2 to 0.7 ml/min, flow per unit of atrial mass was much higher (4 to 12 mV100 gm/min) and may have minimized atrial ischemia. This may explain why, in these experiments as in clinical practice, the atria continued to beat throughout the period of aortic cross-clamping. Noncoronary collateral flow to the left ventricle may explain why cessation of ventricular contraction is often delayed when the aorta is cross-clamped and coronary flow interrupted. While this noncoronary collateral flow may not perfuse a left ventricle adequately, it would wash out any “physiological solution” placed in the coronary circulation to induce cardioplegia and prevent maintenance of a predetermined electrolyte environment within the myocardium. In an attempt to manipulate noncoronary sources of myocardial perfusion, we varied perfusion pressure and blood viscosity during cardiac arrest with aortic cross-clamping. Although flows ranging between 2 and 6 mllmin occurred in 4 of 8 dogs with chronic coronary occlusion when perfusion pressure was 100 mm Hg, negligible coronary flow from noncoronary sources occurred when perfusion pressure was lowered to 50 mm Hg (0.07 m1/100 gmlmin). When blood viscosity was reduced by lowering hematocrit from 40% to 20%, flow increased only 1 m1/100 gm/min. Since the added flow did not make up for the reduced oxygencarrying capacity resulting from hemodilution, there was less oxygen delivery to the myocardium through noncoronary sources despite a higher flow rate. While we expected to find more noncoronary collateral flow in dogs with chronic circumflex occlusion, the amount of this flow during cardiac arrest varied and was comparable to that found in Group I dogs. The stimulus for enlargement of these noncoronary collateral vessels may have been diminished by the development of direct collaterals from other coronary vessels [6, 91. Intercoronary collaterals were seen on the surface of the heart as well as by angiogram (see the VOL. 19, NO. 4, APRIL, 1975
433
BRAZIER, HOTTENROTT, AND BUCKBERG Figure). The adequacy of these intercoronary collateral channels in the beating, working heart is evident from the comparable flows which were measured in the left ventricular apex (supplied by the patent anterior descending coronary artery) and base (supplied through collateral vessels). This collateral flow was distributed equally to the outer and inner shells of the ventricular apex and base (endocardiallepicardial ratio = 1 : 1). Perhaps occlusion of the left anterior descending and circumflex coronary arteries with ameroid constrictors would have simulated more closely the clinical conditions under which noncoronary collateral flow develops from extracoronary sources. The presence of significant amounts of noncoronary flow (12 and 16 m1/100 gmlmin) in hypertrophied hearts and the variable flows ranging from 0.25 to 13 mllmin in both normal dogs and those with chronic circumflex occlusion show that the heart is ischemic but not anoxic when the aorta is cross-clamped. While these flows may not provide sufficient oxygen to meet basal metabolic needs of hearts arrested under normothermia, myocardial oxygen requirements can be decreased significantly with hypothermia. (The oxygen needs of the arrested heart are approximately 2 m1/100 gmlmin [16] and fall markedly as myocardial temperature is lowered [8].)A flow of 6 mllmin from noncoronary collateral sources may therefore provide sufficient oxygen to meet the metabolic requirements of the arrested left ventricle under hypothermia (22°C).These observations may explain why myocardial damage apparently does not occur in some hearts that are arrested for periods from 40 to 120 minutes during intracardiac repair [ 101. The lack of correlation between ischemic injury and duration of arrest may be related to the variable presence of noncoronary collateral flow; cross-clamp time therefore may not be synonymous with anoxia time. Unfortunately, we cannot at this time assess the amount of potential noncoronary collateral flow under clinical conditions.
References 1. Archie, J. P. Determinants of intramyocardial pressure. J Surg Res 16:215, 1974. 2. Baird, R. J., Maklelon, R. T., Shah,$'. A., and Ameli, F. M. Intramyocardial pressure: Study of its regional variations and its relationship to intraventricular pressure. J Thorac Cardiovasc Surg 59:810, 1970. 3. Bloor, C. M., and Liebow, A. A. Coronary collateral circulation. AmJ Cardiol 16238, 1965. 4. Buckberg, G. D., Luck, J. C., Payne, D. B., Hoffman, J. I. E., Archie, J. P., and Fixler, 5. 6. 7. 8. 9.
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D. E. Some sources of error in measuring regional blood flow with radioactive microspheres. J Appl Physiol 31:598, 1971. Domenick, R. J., Hoffman, J. I. E., Noble, M. I. M., Sander, K. B., Henson, J. R., and Subijanto, S. Total and regional coronary blood flow measured by radioactive microspheres in conscious and anesthetized dogs. Circ Res 25:581, 1969. Eckstein, R. W. Effect of exercise and coronary artery narrowing on coronary collateral circulation. Circ Res 5:230, 1957. Fixler, D. E., Wheeler, M., and Huffines, D. Extent of myocardial flow from luminal collateral circulation. J Appl Physiol (In press.) Fuhrman, G. J., Fuhrman, F. A., and Field, J. Metabolism of rat heart slices, with special reference to effects of temperature and anoxia. Am J Physiol 163:642, 1950. Fulton, W. F. M. The dynamic factor in enlargement of coronary arterial anastomoses, and paradoxical changes in the subendocardial plexus. Br Heart J 26:39, 1964.
THE ANNALS OF THORACIC SURGERY
Noncoronary Collateral Myocardial Blood Flow 10. Griepp, R. B., Stinson, E. B., and Shumway, N. E. Profound local hypothermia for myocardial protection during open-heart surgery. J Thorac Cardiovasc Surg 66:73 1, 1973. 1 1 . Griggs, D. M., Tihokoev, V. V., and ChiChen, C. Transmural differences in ventricular tissue substrate levels due to coronary constriction. A m j Physiol222:705, 1972. 12. Halpern, M. H. Arterial supply to the nodal tissue in the dog heart. Circulation 9:547, 1954. 13. Hottenrott, C. E., Towers, B., Kurkji, H. J., Maloney, J. V., and Buckberg, G. The hazard of ventricular fibrillation in hypertrophied ventricles during cardiopulmonary bypass. J Thorac Cardiovusc Surg 66:752, 1973. 14. Hudson, C. L., Moritz, A. R., and Wearn, J. T. The extracardiac anastomoses of the coronary arteries. SOCExp Med 56:919, 1932. 15. Kline, J. L., Stern, H., Bloomer, W. E., and Liebow, A. A. The application of an induced bronchial collateral circulation to the coronary arteries by cardiopneumonopexy. Am J Pathol32:663, 1956. 16. McKeever, W. P., Gregg, D. E., and Canney, P. C. Oxygen uptake of the nonworking left ventricle. Circ Res 7:612, 1958. 17. Moggio, R. A., Kabemba, J. M., and Hammond, G. L. Coronary-ventricular lumen blood exchange demonstrated by %r-labeled erythrocytes. Am J Physiol 221:955, 1971. 18. Moir, T. W. Study of luminal coronary collateral circulation in the beating canine heart. Circ Res 24:735, 1969. 19. Moir, T. W., and DeBra, D. W. Measurement of the endocardial distribution of left ventricular coronary blood flow by Rbs6 chloride. Am Heart J 69:795, 1965. 20. Rudolph, A. M., and Heymann, M. A. Circulation of the fetus in utero: Methods for studying distributions of blood flow, cardiac output and organ blood flow. Circ Res 21:163, 1967. 21. Sayen, J. J., Pierce, G., Katcher, A. H., and Sheldon, W. F. Correlation of intramyocardial electrocardiograms with polarographic oxygen and contractility in the non-ischemic and regionally ischemic left ventricle. Circ Res 9: 1268, 196 1 . 22. Thorel, C. H. Pathologie der Kreislauforgane. Ergeb Allg Pathol Pathol Anat 9:559, 1903. 23. Wearn, J. T., Mettier, S. R., Klumpp, T. G., and Zschiesche, L. J. The nature of the vascular communications between the coronary arteries and the chambers of the heart. Am Heart J 9: 143, 1933.
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ABSTRACT This study shows that noncoronary collateral flow occurs in normal hearts after chronic coronary occlusion and with left ventricular hypertrophy in variable amounts (0.2 to 16 ml/lOO gmlmin). Luminal-left ventricular flow is negligible in the working heart. Nonluminal noncoronary collateral flow is greatest when the heart is arrested by aortic cross-clamping, falls significantly when perfusion pressure is lowered to 50 mm Hg, and increases slightly when blood viscosity is reduced (hemodilution).Our findings indicate that the heart which is arrested by aortic cross-clamping may not be anoxic.
C
ardiac arrest is induced when coronary flow is interrupted by cross-clamping the aorta; a quiet, dry operative field is thus obtained for intracardiac operations. Occasionally, however, the heart does not stop beating or continues to fibrillate despite aortic cross-clamping. These observations suggest that the myocardium may not be anoxic when coronary flow is interrupted and that it receives nourishment from another source. Evidence for extracoronary collateral flow is provided by an occasional outpouring of arterial blood from the coronary ostia when the aorta is opened during valve replacement or from the coronary artery when it is incised during revascularization. This flow occurs in the arrested heart despite adequate venting of the left ventricle and decompression of the coronary sinus to prevent retrograde flow. Other evidence suggestive of extracoronary collateral flow is provided by the excellent ventricular function sometimes seen in patients with complete occlusion of the three major coronary vessels. While the source of the collateral flow is uncertain, some believe it originates from the ventricular lumen and proceeds directly into the myocardium [17, 18, 231. This study was designed to determine if noncoronary collateral flow (1) occurs, (2) is greater in hearts that are ischemic or hypertrophied, (3) can be affected by changes in perfusion pressure of blood viscosity during aortic crossclamping, and (4) originates from the ventricular lumen.
Methods Studies were performed in 22 tnongrel dogs weighing 15 to 25 kg and separated into three experimental groups. From the Division of Thoracic Surgery, UCLA School of Medicine, L a s .\ngeles, Calif. Accepted for publication Nov. 5 , 1974. Supported by grants-in-aid from the U.S. Public Health Service. Blalock Found;ition. M'ilbur \ l a \ Foundation, Frank W. Clark, Jr., Charities, and Beaumont Foundation. Address reprint requests to Dr. Buckberg, Division of Thor;iric Surgery. L1CL.A School o f Medicine, Los Angeles, Calif. 90024.
426
T H E ANNALS OF THOKACIC SUKGEKY
Noncoronary Collateral Myocardial Blood Flow Group I (acute). This group comprised 12 dogs in which no prior operation had been performed. Group I1 (chronic coronary occlusion).Six to eight months prior to the study, 12 dogs underwent left thoracotomy (under fluothane anesthesia) and an ameroid constrictor was placed around the proximal circumflex coronary artery; the 8 surviving animals were included in the present experiments. Group I11 (left ventricular hypertrophy). Five to seven months before this study, 6 dogs underwent median sternotomy (under fluothane anesthesia) and the supravalvular aorta was constricted (60 to 90 mm gradient) to produce left ventricular hypertrophy [ 131; 2 surviving dogs were studied. EXPERIMENTAL PREPARATION
Anesthesia was induced with morphine, 3 mg per kilogram of body weight intramuscularly, and chloralose, 15 mg per kilogram intravenously. Respiration was maintained with an endotracheal tube and positive-pressure respirator. Following bilateral thoracotomy, polyethylene catheters were placed into the ascending aorta, femoral artery, left atrium, and coronary sinus. Pressures were recorded with a Statham P23DB pressure transducer on a Hewlett-Packard multichannel recorder. Cardiopulmonary bypass was instituted by diverting superior and inferior vena caval blood into a bubble oxygenator primed with whole blood and returning it into the femoral artery under normothermic conditions. The left ventricle was vented with a catheter placed through the left atrial appendage, and the right ventricle with a catheter placed directly into the outflow tract. Ventricular pressure was recorded continually to assure adequacy of venting. Regional myocardial blood flow was measured by determining the myocardial distribution of 8- to 10-p microspheres labeled with cerium 141, strontium 85, and scandium 46. A reference sample was collected from a peripheral artery during each microsphere injection. After the procedure the dogs were killed with magnesium sulfate; the hearts were then removed and separated into left and right atria, right ventricle, intraventricular septum, and left ventricular free wall. The left ventricular free wall was further divided into two parts: the region perfused by the left anterior descending coronary artery (apex), and the region perfused by the left circumflex coronary artery (base).The left ventricle sections were then further subdivided into subendocardial, subepicardial, and midmyocardial layers of approximately equal thickness. Total and regional flows were calculated from the equation:
where Fl, is flow to the heart, CI,is counts in the heart, F, is flow in the reference saniple (iiil/min), antl C , .is counts in the reference sample [5, 201. Flows were reported o n l y when there was a ininiinum o f 400 microspheres in both the i.efei.ence sample antl tissue specimen, since this is the minimum number of sphei.es necessary for accurate flow ineasureinent [4].
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427
BRAZIER, HOTTENROTT, AND BUCKBERG Hemoglobin was measured by the cyanohemoglobin method, pH and PCOZ by the Astrup method, and arterial venous Po2 and oxygen content by the Severinghaus method. The pH was between 7.35 and 7.45 in all studies, and Po2 was maintained above 100 mm Hg. Hematocrit was maintained at 40% by adding blood to the reservoir. When hemodilution was used, hematocrit was reduced to 20% by exchanging reservoir blood for Ringer’s lactate solution. EXPERIMENTAL PROCEDURE
Beating, Working Heart. In all dogs, microsphere injections were made under control conditions with the heart beating and doing external work and prior to institution of cardiopulmonary bypass; mean aortic blood pressure was maintained at 100 mm Hg by either withdrawal or addition of blood. To assess the possible presence of noncoronary collateral blood flow, we studied 4 dogs with chronic coronary occlusion in whom the left ventricle was perfused with non-microsphere-containing blood. The left main coronary artery was dissected and a tape passed around it (above the septa1branch), and the right coronary artery was encircled with a tape close to its aortic origin. Using cardiopulmonary bypass, a femoral vein graft was sewn end-to-side into the left anterior descending coronary artery, and the proximal end was connected to a reservoir containing oxygenated blood. Cardiopulmonary bypass was discontinued and the left main coronary artery occluded with a vascular clamp. Perfusion of the heart was maintained with a roller pump by means of the vein graft from the reservoir of oxygenated blood. Coronary perfusion pressure was recorded from a side-branch of a vein graft and was maintained equal to aortic blood pressure (100 mm Hg). The right coronary artery was occluded so that all coronary myocardial flow was provided by the vein graft. Microspheres were injected into the left atrium while the vein graft was perfused with non-microsphere-containing blood from the reservoir at a perfusion pressure of 100 mm Hg. A reference sample was collected simultaneously from the femoral artery. Arrested Heart. Cardiac arrest was produced by occluding both the aorta and pulmonary artery with a vascular clamp placed through the transverse sinus in 12 dogs in the acute group (Group I) and 10with chronic occlusion (Group 11).After we were certain that both ventricles and the supravalvular aorta were empty (zero pressure), we injected microspheres into the perfusion circuit through the femoral perfusion cannula. A reference sample was collected from the contralatera1 femoral artery. During cardiac arrest, perfusion pressure was lowered from 100 to 50 mm Hg in 3 Group I dogs and the microsphere injection was repeated. In addition, blood viscosity was reduced in 7 Group I1 dogs (those with ameroid constrictors) by diluting the perfusion reservoir with Ringer’s lactate solution until the hematocrit was lowered to 20%. Microsphere injections were made at this lowered hematocrit.
Results
At operation, extensive collateral vessel formation was seen on the surface of the heart in all dogs in which an ameroid constrictor had been placed around the 428
THE ANNALS OF THORACIC SURGERY
Noncoronary Collateral Myocardial Blood Flow Proximal LCA , 7 \ \, < , Ameroid
Arteriogram and drawing ofpostmortem coronary angiogram made after injection of Hypaque into the vein graft. Note ( I ) occlusion of the left circumflex coronary artery (LCA) by the ameroid constrictor, and (2) the intercoronary collaterals from the left anterior descending (LAD) artery to the left circumflex coronary artery. This extensive collateralformation explains the normal distribution of coronaryflow under resting conditions despite total occlusion of the 1eJ circumflex coronary artery.
left circumflex coronary artery. These collaterals originated from the left anterior descending and right coronary arteries. They were demonstrated by postmortem angiograms obtained by injection of Hypaque into the vein graft while the main left coronary arteries were occluded (Figure). T h e posterior papillary muscle was scarred in 2 dogs. Beating, Working Heart. Total left ventricular coronary flow was similar in Group I dogs (85 f 17 ml per 100 gm of tissue per minute), in dogs with chronic circumflex occlusion, Group I1 (108 iz 17 mVlOO g d m i n ) , and in the 2 dogs with left ventricular hypertrophy, Group I11 (83 mV100 gm/min) (Table 1). T h e left and right atria received flows ranging from 15 to 80 m1/100 gmlmin in both Group I and Group I1 dogs. Since the atrial mass is low, the actual mean atrial flow was only 7 ml/min in the beating heart. Equal amounts of left ventricular flow were delivered to the area in the distribution of the left anterior descending coronary artery (apex) and left circumflex coronary artery (base) in all studies. T h e apexlbase flow ratio was 1.07 in Group I dogs and 1.07 in dogs with chronic coronary artery occlusion; a similar ratio was seen in dogs with left ventricular hypertrophy (1.02). Coronary flow was distributed evenly across the myocardial wall of the left ventricular apex and base in all groups (endocardial/epicardial flow ratio: Group I, 1.12; chronic coronary occlusion group, 1.03; and group with left ventricular hypertrophy, 1.10) ( p > 0.5). While nutritive flow to the beating, working left ventricle averaged 102 m1/100 gm/min in dogs with chronic coronary artery obstruction (Group 11), the maximum flow delivered from noncoronary sources was 0.25 ml/100 gm/min when the left coronary artery was perfused with non-microsphere-containing blood at a perfusion pressure of 100 mm H g (Table 2). Only 1 of 4 hearts received more than 400 microspheres despite the presence of more than 7,000 microspheres in the reference sample in each study (collected at 5 ml/min). Flow as low VOL. 19, NO. 4, APRIL, 1975
429
BRAZIER, HOTTENROTT, AND BUCKBERG T.\BLE 1.
RESC'LTS IN BE..ZTING, WORKING HEART UNDER NORMAL. PERFUSION
(;t~ollp I - acute
(S = 3)
- chiwnic circuiiifles occl ttsion ( S = 6) 1 1 1 - ventriciil:ir 11ypert t.O),Il! ( S = 2)
11
1.V Flow (nil/ 100 gtii/inin)
1.v .Apex/Base Flow Ratio
8 5 f 17
1 . 0 7 & 0 . 0 9 1.12kO.17
1.6fO.3
42
1.07 ? 0.03
1.03 f 0.09
1.3 & 0 . 1
75 f 27'
1.02
0.97
...
...
108 f 17 79.87
' p < 0.0 1.
1.V
=
left venti.icitl;ir:
E t i t l o = eiitloc;irdi;il:
LV l,eft/Right LA Flow Entlo/Epi Ven tricu lar (mu100 Flow Ratio Flow Ratio gm/min)
Epi = epicartliiil: I..\
=
f
10
left atrial.
as 0.2 mllmin can be measured accuratelywhen the reference sample contains this many spheres 141. Consequently, noncoronary collateral flow in 3 working hearts was too low to measure accurately. When sufficient microspheres were present, left ventricular (LV) flow was distributed evenly across the myocardium (endocardial/epicardial ratio = 1.06)and between the apex and base (apexlbase = 1.03) but totalled only 0.25 mlll00 gmlmin. Arrested Heart. The values for total and regional noncoronary collateral flow are shown in Table 3. Sufficient microspheres were present in the myocardium to calculate noncoronary collateral LV flow in 5 of 12 Group I dogs, 4 of 8 Group I1 dogs, and both Group I11dogs. In Group I dogs left ventricular noncoronary collateral flow was 2 and 13 mllmin, respectively, in 2 dogs and less than 0.4 m1/100 gmlmin in the 3 other dogs in which sufficient microspheres were present to measure flow accurately. Left ventricular flow was 0.6,2.0,5.0, and 5.6 m1/100 gm/min, respectively, in the 4 dogs with chronic left circumflex coronary occlusion (Group 11). The highest total left ventricular flow originating from noncoronary collateral sources occurred in the 2 dogs with left ventricular hypertrophy (12 and 16 m1/100 gmlmin, respectively). Atrial arrest was always delayed when compared with ventricular arrest. In some dogs the atria continued to beat for up to 30 minutes after the ventricle stopped contracting. The left and right atria received an average of 4 m1/100 gmlmin (total flow 0.2 mllmin) in Group I dogs and 12 m1/100 gmlmin (total flow 0.7 mllmin) in dogs with circumflex occlusion, Group I1 (p > 0.01). Left and right atrial flows could be measured and were comparable in all studies. During arrest the left ventricle received twice as much noncoronary collateral flow as the right ventricle (left ventriclelright ventricle flow ratio = 2.6 during arrest and 1.5 in the beating heart with normal coronary perfusion). This noncoronary collateral flow, however, was relatively evenly distributed between the left ventricular apex and base (left anterior descending and circumflex coronary artery distribution) in all studies. There was therefore no increase in collateral flow to the left ventricular base which had its nutrient channel occluded by the ameroid constrictor (see Table 3). The flow delivered to both the apical and basal 430
THE ANNALS OF THORACIC SURGERY
Noncoronary Collateral Myocardial Blood Flow
portions of the heart was also evenly distributed between the inner and outer shells of the ventricle. Lowering perfusion pressure from 100 to 50 mm Hg resulted in almost total cessation of all noncoronary collateral flow to the left ventricle in each of 3 Group I dogs in which flow had been present at higher perfusion pressure (0.07 m1/100 gmlmin). Although reducing the hematocrit to 20%(perfusion pressure 100 mm Hg) resulted in an increase in noncoronary collateral flow in 4 of 7 dogs with chronic coronary occlusion, the flow increment averaged only 1 ml/min and the flow distribution did not change (Table 4).With hemodilution, coronary flow increased less than oxygen-carrying capacity fell.
Comment The possible occurrence of noncoronary collateral myocardial blood flow was noted first by Thebesius in 1708 when he described openings in the inner walls of the atria and ventricles. Although the potential for collateral flow from the left ventricular lumen to its inner shell is possible anatomically, physiological considerations suggest that the left ventricular cavity is an unlikely source of nutrient blood supply to the subendocardium [ 1,2]. Intramyocardial compressive forces in the subendocardium are equal to or exceed intracavitary pressure during systole
VOL. 19, NO. 4, APRIL, 1975
43 1
BRAZIER, HOTTENROTT, AND BUCKBERG and would therefore retard flow from the lumen to the wall during myocardial contraction. During diastole, coronary blood pressure exceeds the cavitary pressure so that the gradient for flow would be from the coronary arteries to the cavity rather than in the reverse direction. If these collateral channels were important, we would expect subendocardium to be the part of the heart least vulnerable to ischemic injury, rather than the area that is injured most when coronary blood supply is inadequate [ 1 1, 2 11. Attempts to quantitate noncoronary collateral myocardial flow with diffusible indicators are difficult to assess since penetration of the myocardium by means of perfusion cannot easily be differentiated from penetration by diffusion. Studies by Moir and DeBra [19] comparing the movement of radioiodinated albumin (l 3 I I ) particulate indicators with rubidium 86 diffusible indicators show that diffusion rather than movement through vascular channels is the way that rubidium enters the endomyocardium. Fixler and associates 171 recently studied noncoronary collateral flow using 8- to 10-/.tradioactive microspheres and found that the maximum noncoronary flow, even with experimental coronary occlusion, is only 0.15 m1/100 gmlmin. We found a similarly minute, noncoronary collateral flow in our study in which the working left ventricle was perfused with nonmicrosphere-containing blood (< 0.25 m1/100 gmlmin in each of 4 dogs). The microsphere method allows for accurate flow measurement if a minimum of 400 spheres is present in both the region of interest and the reference sample. In each of our studies the reference sample contained more than 7,000 microspheres (collected at 5 ml/min). Consequently we could expect to accurately measure flows as low as 0.2 mllmin. The absence of microspheres in the beating, working heart when the coronary arteries were perfused with nonmicrosphere-containing blood is therefore due to the absence of flow from noncoronary sources rather than a limitation of the microsphere method. Conclusions could not be drawn about the precise origin of this slight amount of extracoronary collateral flow in the working heart because sources of potential TABLE 4. EFFECTS OF VARYING PERFUSION PRESSURE AND VISCOSITY ON NONCORONARY COLLATERAL FLOW
Aorta Cross-Clamped Group I - acute Perfusion pressure = 100 mm Hg (N = 5) Perfusion pressure = 50 mm Hg (N = 3) Group I1 - chronic circumflex occlusion Hematocrit = 40% (N = 4) Hematocrit = 20% (N = 4)
LV Flow (mV100 gm/min)
LefdRight LV LV ApedBase Endo/Epi Ventricular Flow Ratio Flow Ratio Flow Ratio
3.32 5.6
1.062 0.69 1.07k 0.56
2.2k 0.5
0.0720.03*
1.1720.49 1.14k0.89
1.7+ 1.2
3.3k 2.4 4.3 2 3.5*
0.96+ 0.71 0.862 0.62 1.32 2 1.00 0.85 2 0.37
2.62 0.5 1.8 +- 0.6
*p < 0.01.
LV = left ventricular; Endo = endocardial; Epi = epicardial.
432
THE ANNALS OF THORACIC SURGERY
Noncoronary Collateral Myocardial Blood Flow noncoronary collateral flow other than the ventricular lumen are known to occur. Several studies have shown that extracoronary collateral vessels arising from mediastinal, pericardial, and bronchial collateral channels enter the heart through pericardial reflections surrounding pulmonary and systemic veins as well as from vasa vasorum along the major vessels leading to and from the myocardium [3, 12, 14, 15, 221. In designing the present study, we simulated clinical conditions in which noncoronary collateral flow is encountered (i.e., chronic myocardial ischemia o r left ventricular hypertrophy), made comparisons with normal hearts, and separated luminal-mural flow from other extracoronary collateral sources. In all studies, flow delivered from noncoronary collaterals was greatest (up to 16 ml/ 100 gm/min) when the heart was arrested by aortic cross-clamping. This observation supports the conclusion that ventricular-luminal flow is not a significant source of extracoronary collateral blood supply; the ventricles could not provide nutrient flow since their cavities were emptied, the heart generated no pressure, and ebb and flow could not occur due to cardiac arrest. We found that the highest proportion of noncoronary collateral flow was always delivered to the atria, which receive up to 30% of their resting flow (beating, working heart) from noncoronary sources during aortic cross-clamping. While total atrial flow was only 0.2 to 0.7 ml/min, flow per unit of atrial mass was much higher (4 to 12 mV100 gm/min) and may have minimized atrial ischemia. This may explain why, in these experiments as in clinical practice, the atria continued to beat throughout the period of aortic cross-clamping. Noncoronary collateral flow to the left ventricle may explain why cessation of ventricular contraction is often delayed when the aorta is cross-clamped and coronary flow interrupted. While this noncoronary collateral flow may not perfuse a left ventricle adequately, it would wash out any “physiological solution” placed in the coronary circulation to induce cardioplegia and prevent maintenance of a predetermined electrolyte environment within the myocardium. In an attempt to manipulate noncoronary sources of myocardial perfusion, we varied perfusion pressure and blood viscosity during cardiac arrest with aortic cross-clamping. Although flows ranging between 2 and 6 mllmin occurred in 4 of 8 dogs with chronic coronary occlusion when perfusion pressure was 100 mm Hg, negligible coronary flow from noncoronary sources occurred when perfusion pressure was lowered to 50 mm Hg (0.07 m1/100 gmlmin). When blood viscosity was reduced by lowering hematocrit from 40% to 20%, flow increased only 1 m1/100 gm/min. Since the added flow did not make up for the reduced oxygencarrying capacity resulting from hemodilution, there was less oxygen delivery to the myocardium through noncoronary sources despite a higher flow rate. While we expected to find more noncoronary collateral flow in dogs with chronic circumflex occlusion, the amount of this flow during cardiac arrest varied and was comparable to that found in Group I dogs. The stimulus for enlargement of these noncoronary collateral vessels may have been diminished by the development of direct collaterals from other coronary vessels [6, 91. Intercoronary collaterals were seen on the surface of the heart as well as by angiogram (see the VOL. 19, NO. 4, APRIL, 1975
433
BRAZIER, HOTTENROTT, AND BUCKBERG Figure). The adequacy of these intercoronary collateral channels in the beating, working heart is evident from the comparable flows which were measured in the left ventricular apex (supplied by the patent anterior descending coronary artery) and base (supplied through collateral vessels). This collateral flow was distributed equally to the outer and inner shells of the ventricular apex and base (endocardiallepicardial ratio = 1 : 1). Perhaps occlusion of the left anterior descending and circumflex coronary arteries with ameroid constrictors would have simulated more closely the clinical conditions under which noncoronary collateral flow develops from extracoronary sources. The presence of significant amounts of noncoronary flow (12 and 16 m1/100 gmlmin) in hypertrophied hearts and the variable flows ranging from 0.25 to 13 mllmin in both normal dogs and those with chronic circumflex occlusion show that the heart is ischemic but not anoxic when the aorta is cross-clamped. While these flows may not provide sufficient oxygen to meet basal metabolic needs of hearts arrested under normothermia, myocardial oxygen requirements can be decreased significantly with hypothermia. (The oxygen needs of the arrested heart are approximately 2 m1/100 gmlmin [16] and fall markedly as myocardial temperature is lowered [8].)A flow of 6 mllmin from noncoronary collateral sources may therefore provide sufficient oxygen to meet the metabolic requirements of the arrested left ventricle under hypothermia (22°C).These observations may explain why myocardial damage apparently does not occur in some hearts that are arrested for periods from 40 to 120 minutes during intracardiac repair [ 101. The lack of correlation between ischemic injury and duration of arrest may be related to the variable presence of noncoronary collateral flow; cross-clamp time therefore may not be synonymous with anoxia time. Unfortunately, we cannot at this time assess the amount of potential noncoronary collateral flow under clinical conditions.
References 1. Archie, J. P. Determinants of intramyocardial pressure. J Surg Res 16:215, 1974. 2. Baird, R. J., Maklelon, R. T., Shah,$'. A., and Ameli, F. M. Intramyocardial pressure: Study of its regional variations and its relationship to intraventricular pressure. J Thorac Cardiovasc Surg 59:810, 1970. 3. Bloor, C. M., and Liebow, A. A. Coronary collateral circulation. AmJ Cardiol 16238, 1965. 4. Buckberg, G. D., Luck, J. C., Payne, D. B., Hoffman, J. I. E., Archie, J. P., and Fixler, 5. 6. 7. 8. 9.
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D. E. Some sources of error in measuring regional blood flow with radioactive microspheres. J Appl Physiol 31:598, 1971. Domenick, R. J., Hoffman, J. I. E., Noble, M. I. M., Sander, K. B., Henson, J. R., and Subijanto, S. Total and regional coronary blood flow measured by radioactive microspheres in conscious and anesthetized dogs. Circ Res 25:581, 1969. Eckstein, R. W. Effect of exercise and coronary artery narrowing on coronary collateral circulation. Circ Res 5:230, 1957. Fixler, D. E., Wheeler, M., and Huffines, D. Extent of myocardial flow from luminal collateral circulation. J Appl Physiol (In press.) Fuhrman, G. J., Fuhrman, F. A., and Field, J. Metabolism of rat heart slices, with special reference to effects of temperature and anoxia. Am J Physiol 163:642, 1950. Fulton, W. F. M. The dynamic factor in enlargement of coronary arterial anastomoses, and paradoxical changes in the subendocardial plexus. Br Heart J 26:39, 1964.
THE ANNALS OF THORACIC SURGERY
Noncoronary Collateral Myocardial Blood Flow 10. Griepp, R. B., Stinson, E. B., and Shumway, N. E. Profound local hypothermia for myocardial protection during open-heart surgery. J Thorac Cardiovasc Surg 66:73 1, 1973. 1 1 . Griggs, D. M., Tihokoev, V. V., and ChiChen, C. Transmural differences in ventricular tissue substrate levels due to coronary constriction. A m j Physiol222:705, 1972. 12. Halpern, M. H. Arterial supply to the nodal tissue in the dog heart. Circulation 9:547, 1954. 13. Hottenrott, C. E., Towers, B., Kurkji, H. J., Maloney, J. V., and Buckberg, G. The hazard of ventricular fibrillation in hypertrophied ventricles during cardiopulmonary bypass. J Thorac Cardiovusc Surg 66:752, 1973. 14. Hudson, C. L., Moritz, A. R., and Wearn, J. T. The extracardiac anastomoses of the coronary arteries. SOCExp Med 56:919, 1932. 15. Kline, J. L., Stern, H., Bloomer, W. E., and Liebow, A. A. The application of an induced bronchial collateral circulation to the coronary arteries by cardiopneumonopexy. Am J Pathol32:663, 1956. 16. McKeever, W. P., Gregg, D. E., and Canney, P. C. Oxygen uptake of the nonworking left ventricle. Circ Res 7:612, 1958. 17. Moggio, R. A., Kabemba, J. M., and Hammond, G. L. Coronary-ventricular lumen blood exchange demonstrated by %r-labeled erythrocytes. Am J Physiol 221:955, 1971. 18. Moir, T. W. Study of luminal coronary collateral circulation in the beating canine heart. Circ Res 24:735, 1969. 19. Moir, T. W., and DeBra, D. W. Measurement of the endocardial distribution of left ventricular coronary blood flow by Rbs6 chloride. Am Heart J 69:795, 1965. 20. Rudolph, A. M., and Heymann, M. A. Circulation of the fetus in utero: Methods for studying distributions of blood flow, cardiac output and organ blood flow. Circ Res 21:163, 1967. 21. Sayen, J. J., Pierce, G., Katcher, A. H., and Sheldon, W. F. Correlation of intramyocardial electrocardiograms with polarographic oxygen and contractility in the non-ischemic and regionally ischemic left ventricle. Circ Res 9: 1268, 196 1 . 22. Thorel, C. H. Pathologie der Kreislauforgane. Ergeb Allg Pathol Pathol Anat 9:559, 1903. 23. Wearn, J. T., Mettier, S. R., Klumpp, T. G., and Zschiesche, L. J. The nature of the vascular communications between the coronary arteries and the chambers of the heart. Am Heart J 9: 143, 1933.
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