Isoproterenol-induced flow responses in mammary and vein bypass grafts

Volume 80,

Number 3

September 1980

THORACIC AND CARDIOVASCULAR SURGERY The Journal of

J

THORAC CARDIOVASC SURG

80:319-326, 1980

Original Communications

Isoproterenol-induced flow responses in mammary and vein bypass grafts To study the relative flow potentials of direct mammary grafts and aorta-coronary artery vein grafts. we measured regional myocardial perfusion (RMP) at rest and following isoproterenol infusion (4 to 8 meg/min) in 53 patients at the time of postoperative coronary arteriography. After the injection of 12 mei of xenon 133 into the coronary artery or graft, washout of the radioactive xenon from the distribution of the artery or graft was measured with a multicrystal scintillation camera. RMP (ml/ /00 gm/min) was calculated with the Kety formula. A response index was calculated (RI = [<1 RMP/ <1 double product] X /0:1) to normalize the data. The patient groups consisted of seven normal subjects (Group 1); 21 patients with vein grafts to the left anterior descending coronary artery (Group 2); 16 patients with internal mammary grafts to the left anterior descending (Group 3); and nine patients with internal mammary grafts to a marginal branch of the circumflex (Group 4). Mean values for resting RMP varied from 80 to 87 ml/ 100 gm/min. In the four groups of patients. RMP following isoproterenol infusion varied from 124 to 14j ml/IOO gm/min. The calculated response index varied from 9.6 to 14.3. The response index in patients with normal wall motion was 12.2 and the response index in the 16 patients with abnormal wall motion was only 5.4. There were no significant differences between the response index of the direct mammary grafts (13) or vein grafts (12.4) to an occluded left anterior descending coronary artery in patients with normal wall motion as compared to the normal circulation (9.8). The data suggest that mammary grafts produce the same flow response to the increased demand of isoproterenol as do vein bypasses and the normal circulation, as long as the distal bed perfused is to normal muscle.

Donald H. Schmidt, M.D. (by invitation), Fred Blau, M.S. (by invitation), Charles Hellman, M.D. (by invitation), Linda Grzelak (by invitation), and W. Dudley Johnson, M.D., Milwaukee. Wis.

From The Cardiovascular Disease Program, Milwaukee Clinical Campus, University of Wisconsin Medical School, Mount Sinai Medical Center, Milwaukee, Wis. Read at the Fifty-ninth Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass., April 30 to May 2, 1979. Address for reprints: Donald H. Schmidt, M.D., Mount Sinai Medical Center, Cardiovascular Disease Section, 950 N. 12th St., Milwaukee, Wis. 53233.

Accumulated clinical experience indicates that the internal mammary artery gives better long-term patency than does the saphenous vein graft for coronary reconstruction.':" Some investigators, however, have advised against using the internal mammary artery graft in patients because of the theoretical fear that these grafts

0022-5223/80/090319+08$00.80/0 © 1980 The C. V. Mosby Co.

319

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Methods

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Fig. 1. The xenon washout technique. Xenon is freely diffusable and enters the capillary bed. Its washout is then proportional to capillary blood flow. A semilogarithmic plot of myocardial xenon 133 activity (CPS/peak CPS against time) is depicted. These counts were obtained by one crystal from a patient. A monoexponential regression is performed on the first 39 seconds of the washout curve. Flow is then computed by the Kety-Schmidt formula. may be flow-limiting at times of peak myocardial demand." 7 Therefore, clarification of the relative flow potentials of direct mammary grafts and aorta-coronary artery vein grafts is clearly desirable. In addition, evidence to support the hypothesis that the coronary bypass graft operation restores the coronary circulation to a normal functional state is fragmentary. 8 This report indicates that nutrient flow in the area distal to vein bypass grafts and internal mammary artery grafts may be normal at rest and, in the presence of normal muscle, responds adequately or the same as the normal coronary circulation to the increased demand produced by an isoproterenol infusion. Furthermore, data will be presented to support the hypothesis that internal mammary artery grafts produce the same flow response to the increased demand of isoproterenol as do vein bypasses.

Regional flow rates in the left ventricular myocardium, as originally described by Cannon, Dell, and Dwyer.?: 10 were measured following the selective injection of 12 mCi of xenon 133 into the left coronary artery or selectively into vein or internal mammary bypass grafts. After it enters the capillary bed, the xenon instantaneously diffuses into the surrounding tissue. Its washout or clearance is then dependent on capillary blood flow (Fig. I). Disappearance of radioactivity from multiple areas of the myocardium was monitored with a multi crystal scintillation camera (Cordis Baird System 77, New Bedford, Mass.) positioned over the chest with the patient in the left anterior oblique position. Nutrient blood flow rates (measured in milliliters per 100 gm per minute) were calculated from the rate constants of isotope clearance by the Kety!' formula, where K is derived, A. equals the partition coefficient of xenon, and p is the specific gravity of myocardium. The regional flow rates were then matched to the coronary arteriogram. The mean or total left ventricular flow was obtained by averaging the local flows recorded by all crystals overlying the left ventricle, normally about 40. Flow to the left anterior descending subregion was obtained by averaging flow in the regions in the distribution of that vessel, and circumflex flow was determined in the same manner. Average flow was also obtained in the subregion perfused by a given vein or internal mammary graft. Fifty-three patients undergoing selective coronary arteriography prior to or following myocardial revascularization were studied after informed consent was obtained in accordance with the guidelines of the institution's human investigation committee. The groups were as follows: Group I, seven normal subjects (two men, five women); Group 2, 21 patients with vein grafts to the left anterior descending coronary artery ( 19 men, two women); Group 3, 16 patients with internal mammary artery grafts to the left anterior descending (13 men, three women); and Group 4, nine patients with internal mammary artery grafts to a marginal branch of the circumflex system (nine men, no women). Five minutes after the artery or graft was selectively visualized, regional myocardial perfusion was measured at rest. The patients were then started on an isoproterenol infusion of 4 to 8 meg/min, the amount gradually being increased to increase the heart rate to about 50% over resting (mean = 120 beats/min). The flow measurement was then repeated. The results were normalized by calculating a response index (RI), which was obtained by dividing the change in regional myo-

Volume 80

Flow responses in mammary and vein bypass grafts

Number 3 September. 1980

32 1

CONTROL ISOPROTERENOL AVERAGE FLOW = 73' AVERAGE FLOW = 121' 'ml/100g/min

Fig. 2. The regional myocardial blood flow response to isoproterenol in a normal subject (Group I). li Flow = Percent increase in regional myocardial perfusion. RI = Response index = ARMP/liDP (heart rate x systolic pressure) x 103 • cardial perfusion (RMP) by the change in demand times 1,000. The double product (DP), namely heart rate times systolic blood pressure, was used as the index of myocardial oxygen demand. RI = li RMP X 103 li DP The ventriculograms performed at the time of coronary arteriography were analyzed as to regional wall motion in the following manner: The right anterior oblique view was divided into an anterolateral, apical, and inferior segment and the left anterior oblique view was divided into an anteroseptal, apical inferior, and posterolateral segment. The ventriculograms were then viewed by two independent observers and the motion of the segments was graded subjectively as to whether the segments were normal, hypokinetic, akinetic, or dyskinetic. Results The response of a patient with a normal left coronary artery given an isoproterenol infusion to increase the heart rate to 125 beats/min is depicted in Fig. 2. The mean myocardial flow over the total left ventricle rose from a control of 73 ml/IOO gm/min to 121 mi/IOO gm/min, which represents a 66% increase and a response index of 11.5. There was a proportional increase in flow iii each subregion. Fig. 3 illustrates the ability of the method to evaluate the distribution and severity of perfusion abnormalities.

This patient had undergone previous coronary bypass for stenosis of the left anterior descending coronary artery. The vein bypass graft had been placed proximal to the stenosis and the anastomosis was stenotic. Analysis of the ventriculogram revealed that distal to the region of the anterior descending stenosis there was decreased wall motion. The patient subsequently underwent another operation and the left internal mammary artery was directly anastomosed side to side to a diagonal branch and end to side into the left anterior descending coronary artery, distal to the noted stenosis. Repeat ventriculography showed improved wall motion. Although the resting flow in the region perfused by the vein bypass graft was normal, the change in flow produced by the isoproterenol infusion represented only a 45% increase, or a response index of 2.5. Also, not enough radioactivity was delivered to the distal distribution of the anterior descending artery to allow us to make a flow determination. Following the second operation, the xenon flow study was repeated with selective injection into the left internal mammary artery bypass graft. Although the control flows measured in the distal distribution of the left anterior descending were low at rest, the flow increased impressively with increased demand, and the response index increased from 2.5 to 4.5. Again, the ventriculogram at the time of this repeat study showed normal wall motion in this subregion. An example of a study done on a vein graft to an occluded left anterior descending coronary artery is il-

The Journal of

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Thoracic and Cardiovascular Surgery

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Fig. 3. The ability of the method to evaluate the distribution and severity of perfusion abnormalities. The vein bypass graft (upper left panel), with the patient filmed in the right anterior oblique projection, was placed proximal to the stenosis and the anastomosis was stenotic. The xenon perfusion study through this vein bypass graft is illustrated in the upper middle panel. The end-diastolic and end-systolic silhouettes of the ventricle are illustrated in the upper right panel. Distal to the region of the anterior descending stenosis, there is decreased wall motion. Following repeat operation, the left internal mammary artery (LIMA) was directly anastomosed side to side to a diagonal branch and end to side to the left anterior descending artery distal to the noted stenosis (lower left panel). The xenon flow study was repeated with selective injection of the left internal mammary bypass graft (middle lower panel). The flow increases with increased demand and the response index changes from 2.5 to 4.5. Repeat ventriculographyshowed improved wall motion as shown in the bottom right panel. RI, Response index. lustrated in Fig. 4. The control study revealed measured perfusion limited to the distribution of the bypass graft. The control flow was 83 ml/100 gm/min, and with isoproterenol it rose to 150 mIl 100 gm/ min, an increase of 81 % with a calculated response index of 14.2. A similar study showing a left internal mammary artery graft to an occluded left anterior descending coronary, although not illustrated, revealed similar findings. In the region perfused by the graft, the control flow, for example, was 79 ml/100 gm/rnin, and with isoproterenol it rose to 123 mIl 100 gm/rnin, an increase of 56% with a calculated response index of 15.9. Similarly, internal mammary artery grafts to a marginal branch of the circumflex artery revealed, for example, a

control flow of 100 mIl 100 gm/min which rose to 146 mIl 100 gm/min with isoproterenol, a 46% increase with a calculated response index of 11.3. The effects of isoproterenol infusion upon the individual patients in the four groups are illustrated in Fig. 5. The mean control flows in all groups are very similar, being approximately 76 ml/lOO gm/min. The mean increase in flow produced with isoproterenol in all groups varied from 125 to 140 mIl 100 gm/min. To further understand the flow data, we analyzed the effect of revascularization on wall motion in these patients, as described earlier, and three patterns were noted (Fig. 6). One pattern was normal motion preoperatively and postoperatively. Another pattern was ab-

Volume 80

Flow responses in mammary and vein bypass grafts

Number 3 September, 1980

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normal anterior wall motion preoperatively, presumably on the basis of ischemia, because postoperatively there was improved anterior wall motion. The third pattern, noted in abnormal, dilated ventricles, was a region of anterior akinesis which remained essentially unchanged following myocardial revascularization. The patients with grafts were then separated into the

30 that had normal wall motion postoperatively (Fig. 7) and the 16 that had abnormal wall motion. The mean response index in the patients with normal wall motion was 12.4. In contrast, the 16 patients with abnormal wall motion had a mean response index of 5.4, a value significantly different (p < 0.001). After excluding the patients with abnormal wall mo-

The Journal of Thoracic and Cardiovascular Surgery

324 Schmidt et al.

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Fig. 7. The relationship of response index to wall motion. The patients with normal wall motion and normal myocardium had a significantly higher response index than those with abnormal motion and. presumably. fibrosis. tion in the region of the left anterior descending coronary or in the distribution of the circumflex, we analyzed the effects of isoproterenol infusion in the four groups of patients (Fig. 8). Mean left ventricular perfusion increased in all groups in response to isoproterenol. There was no significant difference between the groups. The double product, as an index of myocardial demand, rose similarly in all groups during isoproterenol infusion. Analyzing the response index reveals that the flow responses provided by the internal mammary artery grafts were equal to those of vein grafts, and both

There has been considerable discussion about the adequacy and timing of flow in the internal mammary artery graft.P Clinically, in our experience, the flow rates have been adequate to relieve angina from the immediate postoperative period to prolonged follow-up times. Experimental studies in both types of grafts in animals and man at the time of operation indicate that saphenous vein grafts and internal mammary artery grafts have similar flow rates at rest and respond similarly to systemic administration of vasoactive drugs. 13 Other studies have given conflicting results. 7 Given the same arterial blood pressure, graft flow is primarily dependent on the distal vascular bed rather than the conduit. One group of investigators 14 has anastomosed both a saphenous vein graft and an internal mammary artery graft to the same left anterior descending coronary artery in 20 patients and has simultaneously recorded flows and pressure relationships in both bypass conduits. Calculating the supply/demand ratio for left ventricular performance with each bypass independently, they reported the ratio to be two to three times greater with vein grafts than with mammary arteries and concluded that vein grafts have superior hemodynamic capabilities. However, in order for their comparative studies to be valid, the supply/demand ratio for left ventricular performance with various grafts

Volume 80

Flow responses in mammary and vein bypass grafts

Number 3 September, 1980

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Fig. 8. The effects of isoproterenol infusion in the four groups of patients with normal ventricles or normal wall motion in the region of the left anterior descending coronary artery or in the distribution of the circumflex. (The patients with abnormal wall motion are omitted.) Blood flow (regional myocardial perfusion) is illustrated in the left panel, demand (double product) in the middle panel, and response index in the right panel. H.R .. Heart rate. B.P .. Blood pressure.

should be calculated by measuring pressures in the grafted coronary artery downstream from the graft anastomosis rather than in the grafts themselves. Severe spasm of the distal segment of the internal mammary artery has been observed after it is handled for the performance of the anastomosis. However, some 2 weeks later, the segment often appears to have regained its initial width. Thus, it is conceivable that internal mammary artery graft flow measured early after bypass in the operating room, when arterial spasm is maximal, may be lower than the potential flow. 15 This controversy needs further evaluation and, hopefully, this study partially addresses this problem. The success of myocardial revascularization is dependent upon its ability to restore myocardial blood flow to normal physiological properties. Measurement of regional myocardial perfusion with xenon 133 should provide an excellent quantitative means of assessing graft function. Previous studies have demonstrated that the xenon technique is sensitive in detecting reduced regional myocardial perfusion in patients with coronary artery disease and wall motion abnormalities. 16-18 The use of a diffusable tracer has been intended to provide information concerning the flow per unit weight within the segment of myocardium supplied by the bypass graft. Isolation of the segment has been achieved by delivering xenon into the graft. Recirculation is minimal since tracer leaving the heart in the coronary ve-

nous blood is diluted in the remainder of the right heart output and then reduced in concentration in the lungs. Although there are theoretical and practical limitations in the use of diffusable indicators for measuring average flow per unit weight for the entire ventricle and regional flow, we believe this to be the best technique currently available. Our studies concerning flow response in veins are similar to other qualitative approaches, including venous dilution curves after dye injection into the graft and computer-assisted roentgen videodensitometry. Although technically complex, the latter method has considerable potential and its further development will be of interest. Preliminary data by that technique give findings similar to those reported in this study. 19 A study by Lichtlen and associates" showed that regional flows in vein bypass grafts to the left anterior descending artery were slightly lower than, but not significantly different from, flows to the native left coronary artery. This and other studies done in patients with coronary artery disease have employed a bolus injection of xenon 133 with derivation of flow per unit weight from a precordial monoexponential clearance constant.F: 18 The study by Lichtlen and associates, in addition, did measure some flows during exercise, and a previous study using the same technique assessed regional myocardial perfusion during atrial pacing in patients with coronary artery disease. 16 However, these

The Journal of Thoracic and Cardiovascular Surgery

326 Schmidt et al.

studies have not been done with pharmacologic intervention to increase the demand of the ventricle to assess relative flow potentials in bypass grafts. Our data demonstrate that internal mammary artery grafts do respond similarly and as adequately to the increased demand of isoproterenol in the patient 10 to 14 days postoperatively as do saphenous vein bypass grafts. It should be emphasized further that vein bypass grafts are passive conduits, but internal mammary artery grafts are arterial in nature and capable of expanding or shrinking depending on the demand placed on them. Therefore, with time, one would assume that the internal mammary artery would enlarge in response to the needed increased flow. This observation has been partially confirmed by the fact that, in serial follow-up of bypass patients, vein grafts tend to get smaller and internal mammary artery grafts tend to get larger. 3 In summary, we have shown that regional myocardial perfusion distal to a bypassed coronary obstruction is normal at rest and responds normally to the increased oxygen demand produced by an isoproterenol infusion'" if the muscle in the bed perfused is normal. However, if the muscle is abnormal or the graft inadequate, the flow response is diminished. The data also suggest that, within the limits of our experimental design, internal mammary artery grafts to the left anterior descending artery or a marginal branch of the circumflex can meet the demands for increased flow as adequately as vein bypass grafts. We would like to express our thanks for the secretarial assistance provided by Lorna Hendrix and Kathleen Stelling.

2 3

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REFERENCES Kay EB, Naraghipour H, Beg RA, DeManey M, Tambe A, Zimmerman HA: Internal mammary artery bypass graft. Long-term patency rate and follow-up. Ann Thorac Surg 18:269-279, 1974 Barner HB: Double internal mammary-coronary artery bypass. Arch Surg 109:627-630, 1974 Geha AS, Krone RJ, McCormick JR, Baue AE: Selection of coronary bypass. Anatomic, physiological, and angiographic considerations of vein and mammary artery grafts. J THORAC CARDIOVASC SURG 70:414-429, 1975 Geha AS, Baue AE, Krone RJ, Kleiger RE, Oliver GC, McCormick JR, Salimi A: Surgical treatment of unstable angina by saphenous vein and internal mammary artery bypass grafting. J THORAC CARDIOVASC SURG 71:348354, 1976 Favaloro RG: Direct myocardial revascularization. A ten year journey. Myths and realities. Am J Cardiol 43: 109129, 1979 Singh H, Flemma RJ, Tector AJ, Lepley D Jr, Walker JA: Direct myocardial revascularization. Arch Surg 107:699703, 1973

7 Grondin CM, Lesperance J, Bourassa MG, Campeau L: Coronary artery grafting with the saphenous vein or internal mammary artery. Ann Thorac Surg 20:605-618, 1975 8 Kolibash AJ, Goodenow JS, Bush CA, Tetalman MR, Lewis RP: Improvement of myocardial perfusion and left ventricular function after coronary artery bypass grafting in patients with unstable angina. Circulation 59:66-74, 1979 9 Cannon PJ, Dell RB, Dwyer EM Jr: Measurement of regional myocardial perfusion in man with 133xenon and a scintillation camera. J Clin Invest 51:964-977, 1972 10 Cannon PJ, Dell RB, Dwyer EM Jr: Regional myocardial perfusion rates in patients with coronary artery disease. J Clin Invest 51:978-994, 1972 11 Kety SS: Theory of blood-tissue exchange and its application to measurement of blood flow. Meth Med Res 8:223-227, 1960 12 Dobrin P, Canfield T, Moran J, Sullivan H, Pifarre R: Coronary artery bypass. The physiological basis for differences in flow with internal mammary artery and saphenous vein grafts. J THORAC CARDIOVASC SURG 74:445454, 1977 13 McCormick JR, Kaneko M, Baue AE, Geha AL: Blood flow and vasoactive drug effects in internal mammary and venous bypass grafts. Circulation 52:Suppl 1:72-80, 1975 14 Flemma RJ, Singh HM, Tector AJ, Lepley D Jr, Frazier BL: Comparative hemodynamic properties of vein and mammary artery in coronary bypass operations. Ann Thorac Surg 20:619-627, 1975 15 Barner HB: Blood flow in the internal mammary artery. Am Heart J 86:570-571, 1973 16 Schmidt DH, Weiss MB, Casarella WJ, Fowler DL, Sciacca RR, Cannon PJ: Regional myocardial perfusion during atrial pacing in patients with coronary artery disease. Circulation 53:807-819, 1976 17 Dwyer EM Jr, Dell RB, Cannon PJ: Regional myocardial blood flow in patients with residual anterior and inferior transmural infarction. Circulation 48:924-935, 1973 18 See JR, Cohn PF, Holman BL, Roberts BH, Adams DF: Angiographic abnormalities associated with alterations in regional myocardial blood flow in coronary artery disease. Br Heart J 38:1278-1285, 1976 19 Weisz D, Hamby RI, Aintablian A, Voleti C, Fogel R, Wisoff BG: Late coronary bypass graft flow. Quantitative assessment by roentgendensitometry. Ann Thorac Surg 28:429-435, 1979 20 Lichtlen P, Moccetti T, Halter J, Schonbeck M, Senning A: Postoperative evaluation of myocardial blood flow in aorta-to-coronary artery vein bypass grafts using the xenon-residue detection technic. Circulation 46:445-455, 1972 21 Horwitz LD, Curry GC, Parkey RW, Bonte FJ: Effect of isoproterenol on coronary blood flow in primary myocardial disease. Circulation 50:560-564, 1974

(For discussion see page 339.)