REACTIVE HYPEREM\IIA AS AN INDEX TO CORONARY ARTERIAL NARROWING GOTTLIEB C. FRIESINGER, M.D. AND (by inlvitationi) WILLIAM S. HILLIS, M.I)., M.R1.C.P. NASHVILLE1
Coronary arteriography is widely used as a meanis to assess the severity of coronary arteriosclerosis but no readily available technique to determine the functional significance of lesions identified by arteriography is available. In a variety of studies, it has been demonstrated that a severe arterial narrowing, usually greater than 70 %O cross sectional area reduction, is required to alter blood flow or reduce distal pressure.1-6 On coronary arteriograms, it is difficult to measure precisely the severity and length of narrowings, and collaterals may offset the effects of narrowing. Elliott and associates,7 suggested that important changes in coronary blood flow autoregulation might occur with less than so called "critical stenosis" and might limit vascular reactivity during increased blood flow requirements following increased metabolic demand. The current investigation was designed to study the quantitative effects of coronary artery stenoses of known severity and varying lengths. The functional significance of the lesions was judged by a reactive hyperemic response to brief coronary arterial occlusion.8-9
I\IETHODS Experiments were performed in two groups of mongrel dogs. In the first group experiments were performed on 15 anesthetized mongrel dogs. Anesthesia was induced with Pentobarbital, 30 mg/kg, and respiration maintained using a Harvard positive pressure ventilator using room air. A left thoracotomy was performed through the 5th intercostal space, the pericardium incised, and the heart suspended in a pericardial cradle. The proximal portion of the left anterior descending coronary artery was dissected free with preservation of any side branches and a suitably sized electromagnetic flow probe was applied (Carolina Medical Electronics, Inc.). A modified metal Goldblatt clamp (4.5 mm in length) was applied proximal to the flow probe allowing stenoses of varying severity to be created. The reactive hyperemia response to a 15 second occlusion was examined before, as control, and after creation of the stenosis. Records of mean coronary artery flow were recorded at a paper speed of 5 mm/second using a Sanborn 350 recorder. Phasic flows were recorded at 10 mm/second. 198
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A minimum of three minutes between occlusions was allowed so that the flow could return to the pre-occlusion level. Heart rate, measured using a conventional electrocardiogram, aortic pressure, measured using a polyethylene catheter connected to a Statham P23Gb transducer, and aortic flow, measured using an electromagnetic flow probe (Carolina Medical Electronics, Inc.), were recorded to assess preparation stability. These data allowed convenient analysis of the response and calculation of the flow debt, peak reactive hyperemia, total reactive hyperemia, and flow debt repayment as described by Coffman and Gregg (1960). After sacrifice, the heart was removed and the left coronary artery injected using a barium gelatin formalin mixture'0 and post-mortem coronary arteriograms -ere obtained in multiple views. After magnification, the degree of stenosis was assessed and expressed the percentage reduction in cross sectional area compared to the unstenosed vessel proximal to the occluder. In a second series of 10 dogs, the effect of the length of the stenosis on the reactive hypeiemic response was evaluated using the same protocol. Radiolucent plastic screw clamps of 3 mm, 6 mm, and 9 mm lengths were utilized and allowed several degrees of stenosis to be calculated in a single preparation; since selective arterial coronary arteriograms could be performed in the post-mortem specimen and serial narrowings and measurements made.
RESULTS Resting left anterior descending coronary artery flow ranged from 15-40 ml/min. In the control prestenotic state, the temporary occlusion produced a peak reactive flow range of 2.7-7.3 times resting flow. Total reactive hyperemia always overpaid the flow debt, the ratio ranging from 3.4 to 12.2. Increasing the length of a stenosis reduced resting flow at a lesser degree of stenosis. The flow alterations produced by 3 and 4.5 mm narrowings were not significantly different statistically. Stenoses by a 3 mm (or 4.5 mm) clamp reduced resting flow when luminal cross section area was narrowed by 70-93 % (7 observations). Six mm length narrowings reduced resting flow when the cross sectional luminal area was reduced by 56 %, 67 %, and 68 % in three separate studies. Resting flow was reduced by narrowings of 41 % and 60 % in two studies done with a 9 mm length stenosis. Comparing the results in the 3-4.5 mm length narrowings with 6-9 mm length narrowings, the differences in the mean values are significant (p < .05). Figure 1 illustrates the effect of different degrees of stenoses on the total reactive hyperemia, response in animals studied with a 3 mm and 9 mm length narrowiings.
200
GOTTLIEB C. FRIESINGER AND WILLIAM S. HILLIS
n0 (
()
r-
Percentage Stenosis 0 0
L
0
r)
I
a)
2i
Percentage Stenosis
FIG. 1. A plot of total reactive hyperemia against the degree of measured stenosis. Total reactive hyperemia is expressed as the percent of reactive hyperemia during the stenotic period as related to the control. The importance of increasing the length of the stenosis from 3 to 9 mm is clearly demonstrated by the graphs and the accompanying formulh for the line which was derived by the method of least squares.
Regression equations and lines were obtained from these data using the least squares method. These confirmed that the mean values obtained for the 3 mm length were significantly different from the 9 mm length in the range 40-70 % luminal cross section area reduction (p < 0.05). A similar difference was obtained when comparing 3 and 6 mm lengths, but no sig-
AN INDEX TO CORONARY ARTERIAL NARROWING
201
nificant difference was seen between 6 and 9 mm lengths, perhaps related to the small number of observations. DISCUSSION These studies have applied and extended information concerning the influence of arterial narrowing on resting and coronary flow reserve, as elicited using the reactive hyperemic response as a physiological stimulus. Mlann and associates (1) showed that increasing stenosis has the same effect on steady as on pulsatile flow. This suggests that the laws of fluid mechanics, established in vitro, may be applied when considering the influence of a stenosis on arterial flow and pressure. M\lay (2-3) studied the pressure-flow response to increasing stenosis to "critical" levels in vivo, measurinig changes in the iliac arteries of dogs. They found that pressure drop and flow reduction occurred simultaneously and varied inversely with iniereasinig stenosis. Other studies (4) also outline the factors which influence the degree of stenosis which will produce these changes. These factors include the velocity of blood in the prestenotic artery, the cross sectional luminal area of the unstenosed and stenosed vessel and the length of the stenosis. In our study, these factors were evaluated in relation to coronary arterial flow. The results from the 3-4.5 mm length series confirm that severe stenosis (70 %O) is required to reduce mean resting flow. In addition, the 3, 6, and 9 mm length narrowings show that increasing length reduces the severity of lesion required to reduce resting flow and alter the reactive hyperemic response. Hence, these studies demonstrate that measurement of resting flow alone is insensitive to define degrees of narrowing which have potential
functional significance. We utilized temporary occlusion and study of the reactive hyperemic response as a functional test. Release of a 15 second coronary arterial occlusion results in a rapid, predicatable hyperemic response which provides a sensitive and reproducible stimulus to test vascular reactivity (9, 11). Serial responses provoked remarkably reproducible results in this study. The peak hyperemic flow elicited is similar in magnitude to that produced by heavy exercise, excitement or coronary vasodilator administration in the dog (12). 15 second occlusions were chosen because little overall hemodynamic effect and no electrical instability results. Coronary flow returns to its pre-occlusion level within two minutes, allowing repeated study. The results of this study show that the coronary flow reserve as elicited reactive hyperemia is reduced by degrees of stenosis insufficient to alter resting flow. When the narrowing is "critical" i.e., reduces resting flow, the reactive hyperemic response is minimal or completely abolished. This latter finding is in agreement w%ith the observations of others.7 8, 12 The
202
GOTTLIEB C. FRIESINGER AND WILLIAM S. HILLIS
present study provides quantitative information about these relationships. In addition, it demonstrates that when similar degrees of stenosis are applied, increasing the length of stenosis causes additional reduction in the reactive hyperemic response. The mechanism(s) which are responsible for the effects of stenosis on resting coronary flow and reactive hyperemia are not clearly understood. Coronary autoregulation which provides the intrinsic control system to stabilize blood flow and maintain tissue oxygenation may be the explanation.13-'4 In the presence of a constant perfusion pressure, changes in flow are controlled by resistance arterioles and precapillary sphinctors. At rest in an unstenosed vessel, these units have basal myogenic activity. The arterioles show partial constriction and many sphinctors remain closed. In response to increased oxygen demand both elements have the ability to dilate and a potential coronary flow reserve exists. Following the application of a coronary arterial stenosis, resting flow is maintained by vascular relaxation with arteriolar dilatation and an increase in the effective capillary density by recruitment. This occurs in a stepwise fashion with increasing stenosis until maximum peripheral dilatation is present when a further reduction in the arterial lumen is critical and reduces resting flow. During a temporary occlusion in an unstenosed vessel, marked recruitment of capillaries occurs by opening of pre-capillary sphinctors. This allows a massive increase in flow on release." This reactive hyperemia is attenuated following the application of a stenosis as recruitment of some of the reserve capillaries has already occurred. Some of the coronary flow reserve is already "used up" leading to a reduced response on release of the occlusion. The approach and principles used in these experimental studies are applicable to human studies. Flow measurements can be made in the bypass graft at the time of open heart surgery for coronary bypass procedures."6-'8 We have used reactive hyperemia to assess the functional significance of the human coronary atherosclerotic lesions at surgery. We have studied 35 grafts in 21 patients. Details of these studies are not pertinent to the present discussion but data from two patients are presented to illustrate how the experimental use of such studies can enhance the understanding of the functional importance of a coronary bypass. The patients had very similar lesions in the right coronary artery RCA; both had multiple subtotal obstructions proximal to the acute margin of the heart (Fig. 2). Although the flows are different (40 and 65 mls) in the two bypasses to the distal right coronary artery, excellent reactive hyperemia was present in each.* Patient R.C. had a sub-total obstruction of the * It is important to emphasize that measurements were made at least one half hour after cardiopulmonary bypass had been discontinued and after observations in
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203
INTRAOPERATIVE STUDIES-CORONARY BY-PASS SURGERY iHISTORY W. S., 52 F UNSTABLE ANGINA-NORMAL EKG RCA LESIONS MULTIPLE SUBTOTAL OBSTRUCTIONS tiO LCA NARROWINIGS NO COLLATERALS
R. C., 39 M 7 YEARS EPISODIC SYMPTOMS EKG-LAH MULTIPLE SUBTOTAL RCA OBSTRUCTIONS MODERATE LAD NARROWING NO COLLATERALS
RESTING FLOW
PEAK REACTIVE HYPEREMIA
40 mis.
85 mis.
65 mis. 40 mis.
130 mis. NONE
I Fi(-. 2. The figure gives a brief capsule history of two patients. Resting and peak reactive hyperemic flows are shown. The flow measurements showed good reproducibility on repeated measurement. The line drawings of the coronary arterial tree are an attempt to illustrate that the right coronary lesions are similar in both instances. Note that the left anterior descending artery in patient R. C. has a moderately severe proximal lesion and minimal distal lesions. (see text for details)
proximal anterior descending artery in addition to RCA lesions. There was minimal distal disease present in the left anterior descending artery. Flow to the distal anterior descending through the bypass was relatively low, 40 mls, and no reactive hyperemia was present. There are multiple reasons why reactive hyperemia could be absent in this anterior descending bypass. 1) If distal scar were present, it is conceivable that no reactive hyperemia would be present. The absence of electrocardiographic changes in the distribution of the anterior descending artery and the normal appearance of the antero-lateral surface of the ventricle at surgery seemed to preclude this possibility. 2) Adequate collaterals could supply blood and offset the reactive hyperemic response; but none was seen arteriographically. The arteriogram is a gross examination and obviously may not disclose all collateral vessels but this, too, seems an unlikely explanation. the graft had demonstrated the graft flow to be stable. This is an important matter since some published data do not take into consideration the fact that reactive hyperemic response may be absent in the early minutes following discontinuance of cardiopulmonary bypass.
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3) The presence of distal disease makes it conceivable that the presence of distal lesions in the anterior descending is the primary limitation to flow and prevents reactive hyperemia. 4) Another possibility is that the proximal anterior descending lesion, although unequivocally present, is not severe enough to be of physiologic significance. 5) Other explanations seem remote in this particular patient, e.g. the the distal bed was maximumly dilated (reactive hyperemia was already present) but we feel this is not a tenable possibility in light of the fact that the measurements were made long after cardiopulmonary bypass has been discontinued and after the bypass flow has reached a minimum value. Another possibility is that a technical error resulted in narrowing at anastomosis between the bypass and the distal anterior descending and this narrowing prevented increase flow in the bypass graft during the period of reactive hyperemia. Although no definite conclusion can be reached concerning the response in this patient, this kind of intra-operative approach to evaluate the functional significance of a bypass graft would seem useful to pursue. The results of the animal studies suggest that the measurement of the reactive hyperemic response provides an experimental method to determine the quantitative influence of a stenosis on coronary autoregulation even when resting flow is unimpaired. It has clinical relevance and emphasizes that assessment of the hemodynamic importance of a stenosis seen by arteriography must take into account the length, as well as severity of narrowing. 1. 2.
3. 4.
5. 6. 7.
REFERENCES MANN, F. G., BALDES, E. J., ESSEX, H. E. AND HERRICK, J. F.: The effect on the blood flow of decreasing the lumen of a blood vessel. Surgery 4: 249-252, 1938. MAY, A. G., l)EWEESE, J. A., ROB, C. G., AND VAN DE BERG, L.: Critical arterial stenosis. Surgery 54: 250-259, 1963. MxyY, A. G., DEWFESI:, J. A. AND ROB, C. G.: The hemodynamic effects of arterial stenosis. Surgery 53: 513-524, 1963. KINDT, G. W. AND YOUMANS, J. R.: The effect of stricture length on critical arterial stenosis. Surgery, Gynecology and Obstetrics 128: 729-734, 1969. HAIMOVICI, H., AND ZINICOLA N.: Experimental renal artery stenosis diagnostic significance of arterial hemodynamics. Journal of Cardiovascular Surgery 3: 259262, 1962. SCHENK, W. (C., MARTIN, J. W., AND MENNO, A. D.: Hemodynamics of experimental coarctation of the aorta. Annals of Surgery 153: 163-172, 1961. ELLIOTT, E. C., BLOOR, C. M., GREGG, D. E., JONES, E. L., AND LEON, A. S.: Day to day changes in coronary hemodynamics secondary to constriction of the circumflex branch of left coronary artery in conscious dogs. Circulation Research
22: 237-250, 1968. 8. RENEMAN, R. S. AND SPENCER, M. P.: The use of diastolic reactive hyperemia
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9. 10. 11. 12.
13. 14.
15. 16.
17. 18.
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to evaluate the coronary vascular system. Annals of Thoracic Surgery 13: 477487, 1972. OLSSON, R. H. AND GREGG, D. E.: Myocardial reactive hyperemia in the unanesthetized dog. American Journal of Physiology 208: 224-230, 1965. SCHLESINGER, M.D.: New radiopaque mass for vascular injection. Laboratory Investigation 6: 1-11, 1957. COFFMAN, J. D., AND GREGG, D. E.: Reactive hyperemia characteristics of the myocardium. American Journal of Physiology 119: 1143-1149, 1960. KHOURI, E. M., GREGG, D. E., AND LOWENSOHN, H. S.: Flow in the major branches of the left coronary artery during experimental coronary insufficiency in the unanesthetized dog. Circulation Research 23: 99-109, 1968. MELLANDER, S. AND JOHANSSON, B.: Control of resistance, exchange and capacitance functions in the peripheral circulation. Pharmacological Reviews 20: 117196, 1968. JOHNSON, P. C.: Review of previous studies and current theories of autoregulation. Circulation Research Supplement 1: 15-29, 1964. RENKIN, E. M., HUDLICKA, 0. AND SHEEHAN, R. M.: Influence of metabolic vasodilatation on blood tissue diffusion in skeletal muscle. American Journal of Physiology 211: 87-98, 1966. GREENFIELD, J. C., REMBERT, J. C. YOUNG, W. G. AND SABISTAN, D. C.: Studies of blood flow in aorta-to-coronary artery saphenous venous bypass grafts in man. Journal of Clinical Investigation 51: 2724-2735, 1972. STINSON, E. B., OLINGER, E. N., AND GLANCY, D. L.: Anatomical and Physiological determinants of blood flow through aorto-coronary vein bypass grafts. Surgery 74: 3, 390-400, 1973. KREULEN, T. H., KIRK, E. S., GORLIN, R., COHN, L. H. AND COLLINS, J. J.: Coronary artery bypass surgery: Assessment of revascularization by determination of blood flow and mass. American Journal of Cardiology 34: 129-135, 1974.
DISCUSSION DIR. J. MICHAEL CRILEY (Torrance): I was confused by your description of your human model. When you occlude the blood supply, do you occlude both the graft and the parent vessel? If not, it is possible just by occluding the graft that there is actually adequate flow though the left arterior descending branch so that the distal bed was not deprived. DR. FRIESINGER: We did not occlude the native circulation, but I think your conclusion is the one that I must reach on those data, namely, that although the lesion was there, it probably was not of functional significance. DR. F. M. ABBOUD (Iowa City): The data obviously will open up spectrum of coronary artery surgery to include lesions that are less than the so-called critical lesions; i.e. less than 70% occlusion. Are you changing criteria at your institution based on these findings since lesions causing 60 or 50% occlusion may be very limiting during exercise. DR. FRIESINGER: I don't think we have any data which would allow us to change clinical criteria, but I think techniques such as outlined here to study the problem are important. So I have no doubt that people are going to be operated on for a variety of reasons, some scientific, many emotional, but if they are going to be operated I think functional evaluation is of great importance over the next few years. DR. RICHARD S. Ross (Baltimore): This is a very interesting piece of work and certainly adds an important dimension to our interpretation of arteriography. The
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reactive hyperemia response at surgery is open to a lot of different interpretations. The absence of hyperemia can mean that the stenosis isn't very bad or that there is a very good collateral circulation. There is great promise in studies using this same response in the intact person while measuring blood flow with radioactive material. Observations of the total blood flow response to exercise are very valuable. These measurements can be made with radioisotopes such as potassium or Thallium. A resting study is compared with a study performed with the isotope injected during exercise. DR. FRIESINGER: Thank you, we couldn't agree more and actually this particular stutdy is one small part of a package which is aimed at what you suggest we should be doing, namely working on ways to estimate regional flow. The particular technique in which we have an interest is utilization of the gamma camera, but we do feel the need for a dog model where we know rather precisely what's going on. I would only comnment that many people around the country are in fact measuring or making attempts to measure or at least getting information on regional flow but as yet the sensitivity of these techniques which are feasible in humans, the sensitivity limitationis are uinknown. So again I think we need more ample studies. DR. FRANCIS C. WOOD (Philadelphia): There are some people with angina who can do what they call walk through it, namely they keep on going, possibly at slightly slower rate, and then before very long they can continue the exercise that stopped them before. Do you suppose this is evidence of the reactive hyperemia you have been talking about? DR. FRIESINGER: Dr. Wood, I think that is one of the explanations. My personal bias is that these folks that have "walk through" angina probably had their primary adjustment in the peripheral vascular with decreased peripheral vascular resistance in blood pressure and a lower heart rate. Even at the same level or an increased level of exercise and hence reduced myocardial oxygen consumption, but the alternative hypothesis which you put forward, namely reactive hyperemia, occurred as a response to the ischemia and now indeed these folks have myocardial oxygen delivery is certainly tenable.
Coronary arteriography is widely used as a meanis to assess the severity of coronary arteriosclerosis but no readily available technique to determine the functional significance of lesions identified by arteriography is available. In a variety of studies, it has been demonstrated that a severe arterial narrowing, usually greater than 70 %O cross sectional area reduction, is required to alter blood flow or reduce distal pressure.1-6 On coronary arteriograms, it is difficult to measure precisely the severity and length of narrowings, and collaterals may offset the effects of narrowing. Elliott and associates,7 suggested that important changes in coronary blood flow autoregulation might occur with less than so called "critical stenosis" and might limit vascular reactivity during increased blood flow requirements following increased metabolic demand. The current investigation was designed to study the quantitative effects of coronary artery stenoses of known severity and varying lengths. The functional significance of the lesions was judged by a reactive hyperemic response to brief coronary arterial occlusion.8-9
I\IETHODS Experiments were performed in two groups of mongrel dogs. In the first group experiments were performed on 15 anesthetized mongrel dogs. Anesthesia was induced with Pentobarbital, 30 mg/kg, and respiration maintained using a Harvard positive pressure ventilator using room air. A left thoracotomy was performed through the 5th intercostal space, the pericardium incised, and the heart suspended in a pericardial cradle. The proximal portion of the left anterior descending coronary artery was dissected free with preservation of any side branches and a suitably sized electromagnetic flow probe was applied (Carolina Medical Electronics, Inc.). A modified metal Goldblatt clamp (4.5 mm in length) was applied proximal to the flow probe allowing stenoses of varying severity to be created. The reactive hyperemia response to a 15 second occlusion was examined before, as control, and after creation of the stenosis. Records of mean coronary artery flow were recorded at a paper speed of 5 mm/second using a Sanborn 350 recorder. Phasic flows were recorded at 10 mm/second. 198
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199
A minimum of three minutes between occlusions was allowed so that the flow could return to the pre-occlusion level. Heart rate, measured using a conventional electrocardiogram, aortic pressure, measured using a polyethylene catheter connected to a Statham P23Gb transducer, and aortic flow, measured using an electromagnetic flow probe (Carolina Medical Electronics, Inc.), were recorded to assess preparation stability. These data allowed convenient analysis of the response and calculation of the flow debt, peak reactive hyperemia, total reactive hyperemia, and flow debt repayment as described by Coffman and Gregg (1960). After sacrifice, the heart was removed and the left coronary artery injected using a barium gelatin formalin mixture'0 and post-mortem coronary arteriograms -ere obtained in multiple views. After magnification, the degree of stenosis was assessed and expressed the percentage reduction in cross sectional area compared to the unstenosed vessel proximal to the occluder. In a second series of 10 dogs, the effect of the length of the stenosis on the reactive hypeiemic response was evaluated using the same protocol. Radiolucent plastic screw clamps of 3 mm, 6 mm, and 9 mm lengths were utilized and allowed several degrees of stenosis to be calculated in a single preparation; since selective arterial coronary arteriograms could be performed in the post-mortem specimen and serial narrowings and measurements made.
RESULTS Resting left anterior descending coronary artery flow ranged from 15-40 ml/min. In the control prestenotic state, the temporary occlusion produced a peak reactive flow range of 2.7-7.3 times resting flow. Total reactive hyperemia always overpaid the flow debt, the ratio ranging from 3.4 to 12.2. Increasing the length of a stenosis reduced resting flow at a lesser degree of stenosis. The flow alterations produced by 3 and 4.5 mm narrowings were not significantly different statistically. Stenoses by a 3 mm (or 4.5 mm) clamp reduced resting flow when luminal cross section area was narrowed by 70-93 % (7 observations). Six mm length narrowings reduced resting flow when the cross sectional luminal area was reduced by 56 %, 67 %, and 68 % in three separate studies. Resting flow was reduced by narrowings of 41 % and 60 % in two studies done with a 9 mm length stenosis. Comparing the results in the 3-4.5 mm length narrowings with 6-9 mm length narrowings, the differences in the mean values are significant (p < .05). Figure 1 illustrates the effect of different degrees of stenoses on the total reactive hyperemia, response in animals studied with a 3 mm and 9 mm length narrowiings.
200
GOTTLIEB C. FRIESINGER AND WILLIAM S. HILLIS
n0 (
()
r-
Percentage Stenosis 0 0
L
0
r)
I
a)
2i
Percentage Stenosis
FIG. 1. A plot of total reactive hyperemia against the degree of measured stenosis. Total reactive hyperemia is expressed as the percent of reactive hyperemia during the stenotic period as related to the control. The importance of increasing the length of the stenosis from 3 to 9 mm is clearly demonstrated by the graphs and the accompanying formulh for the line which was derived by the method of least squares.
Regression equations and lines were obtained from these data using the least squares method. These confirmed that the mean values obtained for the 3 mm length were significantly different from the 9 mm length in the range 40-70 % luminal cross section area reduction (p < 0.05). A similar difference was obtained when comparing 3 and 6 mm lengths, but no sig-
AN INDEX TO CORONARY ARTERIAL NARROWING
201
nificant difference was seen between 6 and 9 mm lengths, perhaps related to the small number of observations. DISCUSSION These studies have applied and extended information concerning the influence of arterial narrowing on resting and coronary flow reserve, as elicited using the reactive hyperemic response as a physiological stimulus. Mlann and associates (1) showed that increasing stenosis has the same effect on steady as on pulsatile flow. This suggests that the laws of fluid mechanics, established in vitro, may be applied when considering the influence of a stenosis on arterial flow and pressure. M\lay (2-3) studied the pressure-flow response to increasing stenosis to "critical" levels in vivo, measurinig changes in the iliac arteries of dogs. They found that pressure drop and flow reduction occurred simultaneously and varied inversely with iniereasinig stenosis. Other studies (4) also outline the factors which influence the degree of stenosis which will produce these changes. These factors include the velocity of blood in the prestenotic artery, the cross sectional luminal area of the unstenosed and stenosed vessel and the length of the stenosis. In our study, these factors were evaluated in relation to coronary arterial flow. The results from the 3-4.5 mm length series confirm that severe stenosis (70 %O) is required to reduce mean resting flow. In addition, the 3, 6, and 9 mm length narrowings show that increasing length reduces the severity of lesion required to reduce resting flow and alter the reactive hyperemic response. Hence, these studies demonstrate that measurement of resting flow alone is insensitive to define degrees of narrowing which have potential
functional significance. We utilized temporary occlusion and study of the reactive hyperemic response as a functional test. Release of a 15 second coronary arterial occlusion results in a rapid, predicatable hyperemic response which provides a sensitive and reproducible stimulus to test vascular reactivity (9, 11). Serial responses provoked remarkably reproducible results in this study. The peak hyperemic flow elicited is similar in magnitude to that produced by heavy exercise, excitement or coronary vasodilator administration in the dog (12). 15 second occlusions were chosen because little overall hemodynamic effect and no electrical instability results. Coronary flow returns to its pre-occlusion level within two minutes, allowing repeated study. The results of this study show that the coronary flow reserve as elicited reactive hyperemia is reduced by degrees of stenosis insufficient to alter resting flow. When the narrowing is "critical" i.e., reduces resting flow, the reactive hyperemic response is minimal or completely abolished. This latter finding is in agreement w%ith the observations of others.7 8, 12 The
202
GOTTLIEB C. FRIESINGER AND WILLIAM S. HILLIS
present study provides quantitative information about these relationships. In addition, it demonstrates that when similar degrees of stenosis are applied, increasing the length of stenosis causes additional reduction in the reactive hyperemic response. The mechanism(s) which are responsible for the effects of stenosis on resting coronary flow and reactive hyperemia are not clearly understood. Coronary autoregulation which provides the intrinsic control system to stabilize blood flow and maintain tissue oxygenation may be the explanation.13-'4 In the presence of a constant perfusion pressure, changes in flow are controlled by resistance arterioles and precapillary sphinctors. At rest in an unstenosed vessel, these units have basal myogenic activity. The arterioles show partial constriction and many sphinctors remain closed. In response to increased oxygen demand both elements have the ability to dilate and a potential coronary flow reserve exists. Following the application of a coronary arterial stenosis, resting flow is maintained by vascular relaxation with arteriolar dilatation and an increase in the effective capillary density by recruitment. This occurs in a stepwise fashion with increasing stenosis until maximum peripheral dilatation is present when a further reduction in the arterial lumen is critical and reduces resting flow. During a temporary occlusion in an unstenosed vessel, marked recruitment of capillaries occurs by opening of pre-capillary sphinctors. This allows a massive increase in flow on release." This reactive hyperemia is attenuated following the application of a stenosis as recruitment of some of the reserve capillaries has already occurred. Some of the coronary flow reserve is already "used up" leading to a reduced response on release of the occlusion. The approach and principles used in these experimental studies are applicable to human studies. Flow measurements can be made in the bypass graft at the time of open heart surgery for coronary bypass procedures."6-'8 We have used reactive hyperemia to assess the functional significance of the human coronary atherosclerotic lesions at surgery. We have studied 35 grafts in 21 patients. Details of these studies are not pertinent to the present discussion but data from two patients are presented to illustrate how the experimental use of such studies can enhance the understanding of the functional importance of a coronary bypass. The patients had very similar lesions in the right coronary artery RCA; both had multiple subtotal obstructions proximal to the acute margin of the heart (Fig. 2). Although the flows are different (40 and 65 mls) in the two bypasses to the distal right coronary artery, excellent reactive hyperemia was present in each.* Patient R.C. had a sub-total obstruction of the * It is important to emphasize that measurements were made at least one half hour after cardiopulmonary bypass had been discontinued and after observations in
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203
INTRAOPERATIVE STUDIES-CORONARY BY-PASS SURGERY iHISTORY W. S., 52 F UNSTABLE ANGINA-NORMAL EKG RCA LESIONS MULTIPLE SUBTOTAL OBSTRUCTIONS tiO LCA NARROWINIGS NO COLLATERALS
R. C., 39 M 7 YEARS EPISODIC SYMPTOMS EKG-LAH MULTIPLE SUBTOTAL RCA OBSTRUCTIONS MODERATE LAD NARROWING NO COLLATERALS
RESTING FLOW
PEAK REACTIVE HYPEREMIA
40 mis.
85 mis.
65 mis. 40 mis.
130 mis. NONE
I Fi(-. 2. The figure gives a brief capsule history of two patients. Resting and peak reactive hyperemic flows are shown. The flow measurements showed good reproducibility on repeated measurement. The line drawings of the coronary arterial tree are an attempt to illustrate that the right coronary lesions are similar in both instances. Note that the left anterior descending artery in patient R. C. has a moderately severe proximal lesion and minimal distal lesions. (see text for details)
proximal anterior descending artery in addition to RCA lesions. There was minimal distal disease present in the left anterior descending artery. Flow to the distal anterior descending through the bypass was relatively low, 40 mls, and no reactive hyperemia was present. There are multiple reasons why reactive hyperemia could be absent in this anterior descending bypass. 1) If distal scar were present, it is conceivable that no reactive hyperemia would be present. The absence of electrocardiographic changes in the distribution of the anterior descending artery and the normal appearance of the antero-lateral surface of the ventricle at surgery seemed to preclude this possibility. 2) Adequate collaterals could supply blood and offset the reactive hyperemic response; but none was seen arteriographically. The arteriogram is a gross examination and obviously may not disclose all collateral vessels but this, too, seems an unlikely explanation. the graft had demonstrated the graft flow to be stable. This is an important matter since some published data do not take into consideration the fact that reactive hyperemic response may be absent in the early minutes following discontinuance of cardiopulmonary bypass.
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GOTTLIEB C. FRIESINGER AND WILLIAM S. HILLIS
3) The presence of distal disease makes it conceivable that the presence of distal lesions in the anterior descending is the primary limitation to flow and prevents reactive hyperemia. 4) Another possibility is that the proximal anterior descending lesion, although unequivocally present, is not severe enough to be of physiologic significance. 5) Other explanations seem remote in this particular patient, e.g. the the distal bed was maximumly dilated (reactive hyperemia was already present) but we feel this is not a tenable possibility in light of the fact that the measurements were made long after cardiopulmonary bypass has been discontinued and after the bypass flow has reached a minimum value. Another possibility is that a technical error resulted in narrowing at anastomosis between the bypass and the distal anterior descending and this narrowing prevented increase flow in the bypass graft during the period of reactive hyperemia. Although no definite conclusion can be reached concerning the response in this patient, this kind of intra-operative approach to evaluate the functional significance of a bypass graft would seem useful to pursue. The results of the animal studies suggest that the measurement of the reactive hyperemic response provides an experimental method to determine the quantitative influence of a stenosis on coronary autoregulation even when resting flow is unimpaired. It has clinical relevance and emphasizes that assessment of the hemodynamic importance of a stenosis seen by arteriography must take into account the length, as well as severity of narrowing. 1. 2.
3. 4.
5. 6. 7.
REFERENCES MANN, F. G., BALDES, E. J., ESSEX, H. E. AND HERRICK, J. F.: The effect on the blood flow of decreasing the lumen of a blood vessel. Surgery 4: 249-252, 1938. MAY, A. G., l)EWEESE, J. A., ROB, C. G., AND VAN DE BERG, L.: Critical arterial stenosis. Surgery 54: 250-259, 1963. MxyY, A. G., DEWFESI:, J. A. AND ROB, C. G.: The hemodynamic effects of arterial stenosis. Surgery 53: 513-524, 1963. KINDT, G. W. AND YOUMANS, J. R.: The effect of stricture length on critical arterial stenosis. Surgery, Gynecology and Obstetrics 128: 729-734, 1969. HAIMOVICI, H., AND ZINICOLA N.: Experimental renal artery stenosis diagnostic significance of arterial hemodynamics. Journal of Cardiovascular Surgery 3: 259262, 1962. SCHENK, W. (C., MARTIN, J. W., AND MENNO, A. D.: Hemodynamics of experimental coarctation of the aorta. Annals of Surgery 153: 163-172, 1961. ELLIOTT, E. C., BLOOR, C. M., GREGG, D. E., JONES, E. L., AND LEON, A. S.: Day to day changes in coronary hemodynamics secondary to constriction of the circumflex branch of left coronary artery in conscious dogs. Circulation Research
22: 237-250, 1968. 8. RENEMAN, R. S. AND SPENCER, M. P.: The use of diastolic reactive hyperemia
AN INDEX TO CORONARY ARTERIAL NARROWING
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to evaluate the coronary vascular system. Annals of Thoracic Surgery 13: 477487, 1972. OLSSON, R. H. AND GREGG, D. E.: Myocardial reactive hyperemia in the unanesthetized dog. American Journal of Physiology 208: 224-230, 1965. SCHLESINGER, M.D.: New radiopaque mass for vascular injection. Laboratory Investigation 6: 1-11, 1957. COFFMAN, J. D., AND GREGG, D. E.: Reactive hyperemia characteristics of the myocardium. American Journal of Physiology 119: 1143-1149, 1960. KHOURI, E. M., GREGG, D. E., AND LOWENSOHN, H. S.: Flow in the major branches of the left coronary artery during experimental coronary insufficiency in the unanesthetized dog. Circulation Research 23: 99-109, 1968. MELLANDER, S. AND JOHANSSON, B.: Control of resistance, exchange and capacitance functions in the peripheral circulation. Pharmacological Reviews 20: 117196, 1968. JOHNSON, P. C.: Review of previous studies and current theories of autoregulation. Circulation Research Supplement 1: 15-29, 1964. RENKIN, E. M., HUDLICKA, 0. AND SHEEHAN, R. M.: Influence of metabolic vasodilatation on blood tissue diffusion in skeletal muscle. American Journal of Physiology 211: 87-98, 1966. GREENFIELD, J. C., REMBERT, J. C. YOUNG, W. G. AND SABISTAN, D. C.: Studies of blood flow in aorta-to-coronary artery saphenous venous bypass grafts in man. Journal of Clinical Investigation 51: 2724-2735, 1972. STINSON, E. B., OLINGER, E. N., AND GLANCY, D. L.: Anatomical and Physiological determinants of blood flow through aorto-coronary vein bypass grafts. Surgery 74: 3, 390-400, 1973. KREULEN, T. H., KIRK, E. S., GORLIN, R., COHN, L. H. AND COLLINS, J. J.: Coronary artery bypass surgery: Assessment of revascularization by determination of blood flow and mass. American Journal of Cardiology 34: 129-135, 1974.
DISCUSSION DIR. J. MICHAEL CRILEY (Torrance): I was confused by your description of your human model. When you occlude the blood supply, do you occlude both the graft and the parent vessel? If not, it is possible just by occluding the graft that there is actually adequate flow though the left arterior descending branch so that the distal bed was not deprived. DR. FRIESINGER: We did not occlude the native circulation, but I think your conclusion is the one that I must reach on those data, namely, that although the lesion was there, it probably was not of functional significance. DR. F. M. ABBOUD (Iowa City): The data obviously will open up spectrum of coronary artery surgery to include lesions that are less than the so-called critical lesions; i.e. less than 70% occlusion. Are you changing criteria at your institution based on these findings since lesions causing 60 or 50% occlusion may be very limiting during exercise. DR. FRIESINGER: I don't think we have any data which would allow us to change clinical criteria, but I think techniques such as outlined here to study the problem are important. So I have no doubt that people are going to be operated on for a variety of reasons, some scientific, many emotional, but if they are going to be operated I think functional evaluation is of great importance over the next few years. DR. RICHARD S. Ross (Baltimore): This is a very interesting piece of work and certainly adds an important dimension to our interpretation of arteriography. The
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reactive hyperemia response at surgery is open to a lot of different interpretations. The absence of hyperemia can mean that the stenosis isn't very bad or that there is a very good collateral circulation. There is great promise in studies using this same response in the intact person while measuring blood flow with radioactive material. Observations of the total blood flow response to exercise are very valuable. These measurements can be made with radioisotopes such as potassium or Thallium. A resting study is compared with a study performed with the isotope injected during exercise. DR. FRIESINGER: Thank you, we couldn't agree more and actually this particular stutdy is one small part of a package which is aimed at what you suggest we should be doing, namely working on ways to estimate regional flow. The particular technique in which we have an interest is utilization of the gamma camera, but we do feel the need for a dog model where we know rather precisely what's going on. I would only comnment that many people around the country are in fact measuring or making attempts to measure or at least getting information on regional flow but as yet the sensitivity of these techniques which are feasible in humans, the sensitivity limitationis are uinknown. So again I think we need more ample studies. DR. FRANCIS C. WOOD (Philadelphia): There are some people with angina who can do what they call walk through it, namely they keep on going, possibly at slightly slower rate, and then before very long they can continue the exercise that stopped them before. Do you suppose this is evidence of the reactive hyperemia you have been talking about? DR. FRIESINGER: Dr. Wood, I think that is one of the explanations. My personal bias is that these folks that have "walk through" angina probably had their primary adjustment in the peripheral vascular with decreased peripheral vascular resistance in blood pressure and a lower heart rate. Even at the same level or an increased level of exercise and hence reduced myocardial oxygen consumption, but the alternative hypothesis which you put forward, namely reactive hyperemia, occurred as a response to the ischemia and now indeed these folks have myocardial oxygen delivery is certainly tenable.
