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Effects of afterload elevation on the ischemic myocardium in isolated, paced canine heart with partial coronary stenosis
Effects of Afterload Elevation on the lschemic Myocardiurir in Isolated, Paced Canine Heart with Partial Coronary Stenosis Yukio Maruyama, MD, Shogen Isoyama, MD, Kouichi Ashikawa, MD, Shoichi Satoh, MD, Hideyuki Suzuki, MD, Osamu Nishioka, MD, Jun Watanabe, MD, and Tamotsu Takishima, MD
The effect of afterload elevation on the ischemic myocardium was examined in an isolated, paced canine heart with a partial coronary stenosis. The coronary blood flow of the left circumflex coronary artery was reduced to approximately one-third of the values before stenosis. The left circumflex coronary stenosis produced a decrease in global ventricular function, a decrease in systolic shortening and deviation of the ST-segment of the epicardial electrocardiogram,and an increase in myocardial carbon dioxide (CO4 tension of the ischemic region. Then, afterload elevation with constant preload decreased the myocardial CO2 tension and improved the ST-segment deviation of the ischemic myocardium. Mechanical function, estimated by the relation between mean aortic pressure and systolic shortening, also improved with elevation of mean aortic pressure. In contrast, afterload elevation combined with preload elevation did not improve ischemic injury, as estimated by myocardial CO2 tension, and did not improve ST-segment deviation or mechanical function despite an increase in left circumflex coronary flow. These results suggest that the elevation of afterload pressure under constant preload improves ischemia produced by a partial coronary stenosis due to increased coronary blood supply; however, the preload elevation counterbalances the beneficial effects of afterload elevation. (Am J Cardiol 1989;63:40E-44E)
From the First Department of Internal Medicine, Tohoku University School of Medicine, l-l Seiryo-machi, Sendai, 980 Japan. Address for reprints: Tamotsu Takishima, MD, First Department of Internal Medicine, Tohoku University School of Medicine, l-l Seiryo-machi, Sendai, 980 Japan.
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lthough it wasfound that reduction of aortic pressure leads to deterioration of the contractile function of the ischemic myocardium,’ whether elevation of aortic pressure decreases the severity of ischemia has not been fully elucidated. In prior studies,2,3 in which regional ischemia was produced by a complete occlusion of a coronary arterial branch, the elevation of aortic pressure was found to decrease the severity of ischemia except when the aortic pressure was extremely elevateda However, there have been only a few controversial reports4-6 of studies in a heart with an incomplete occlusion. In these studies, mechanical function of the ischemic myocardium was depressed,4 did not changes or was improved,6 and afterload elevation was accompanied by increases in preload and changes in heart rate.5 Accordingly, we attempted to clarify how the elevation of aortic pressure affects ischemic myocardial function under 2 conditions, i.e., first, afterload elevation with constant preload and second, afterload elevation combined with preload elevation. METHODS Surgical
preparation (Fig. 1): Procedures for surgical preparation have been described elsewhere.‘l Thirteen mongrel dogs weighing 13.6 to 18.0 kg (mean 15.1) were used. A Gregg-type cannula was inserted through the brachiocephalic artery to the ascending aorta. Just after starting coronary perfusion with arterial blood from a support dog, the heart was isolated. The cannula was then advanced into the ostium of the left common coronary artery. The adaptor of the hydraulic loading system7p8 was connected to the aorta. In this study, only the peripheral resistance (Rp) value was changed in a stepwise fashion. The mean perfusion pressure was maintained equal to the mean aortic pressure throughout each experiment, as was done in the previous study.7 Coagulation was prevented with heparin (10,000 U initial injection, and 5,000 U every hour thereafter). The hydrogen ion concentration, (pH), partial pressure of oxygen (PO& partial carbon dioxide pressure (PC03 and hemoglobin of the arterial blood of the support dog were maintained within a physiologic range, i.e., 7.37 to 7.51 for pH, 75 to 120 mm Hg for PO;?, and 10.0 to 16.0 g/d1 for hemoglobin. Measurements and calculations: Left ventricular, aortic and perfusion pressures, and aortic, mean left coro-
nary and mean left circumflex coronary blood flows were measured as described previously.7,s Mean coronary blood flow of the left anterior descending artery was calculated by subtracting the value of mean left circumflex coronary flow from mean left coronary flow value. Cardiac output was measured from the amount of saline solution ejected over 20 seconds. To measure regional dimensions, 2 pairs of miniature (1.5 to 2.0 mm in diameter) ultrasonic crystals were implanted subendocardially: 1 in the left circumflex segment in the center of the cyanotic area, and the other in the left anterior descending segment. End-diastolic and end-systolic dimensions were determined as previously performed.7 Systolic shortening was calculated as the difference between these 2 lengths. For electrocardiographic recordings, 2 epicardial electrodes were sutured at the surface of the left ventricle,9 near the ultrasonic crystals. The system for measuring myocardial CO2 tension at the subendocardial layer of the left ventricle has been described elsewhere.lO The linear range of the system was between 10 and 200 mm Hg of CO2 tension and the 90% response time was 45 seconds. Experimental protocols: In protocol 1, the effect on the ischemic myocardium of pure afterload elevation with constant preload was examined; in protocol II, we examined the effect on the ischemic myocardium of afterload elevation combined with preload elevation, since afterload elevation often accompanies preload elevation with only a slight decrease of cardiac output in the clinical situation. In protocol I (n = 8), at a constant left ventricular end-diastolic pressure (6.1 f 1.2 mm Hg) and heart rate (140 f 3 beats/min), the Rp was elevated from 4.1 X 1O3 to 5.3 X lo3 and to 10.7 X lo3 dynes-*cme5 in a stepwise fashion at intervals of 10 minutes. Then, at 4.1 X lo3 dynes+cme5 of Rp, the mean left circumflex coronary flow wasreduced to 33% of the control value (range 24 to 46%) with a screw-driven metal clamp. Ten minutes after stenosis of the left circumflex coronary branch, we observed that a steady-state of hemodynamics and myocardial CO:! tension had been reached. Thereafter, we elevated the value of Rp in the same manner and in the same intervals as previously described. In protocol II (n = 5), the prestenosis data at 5.2 X IO3 dynepscme5 of Rp and 6.5 f 0.7 mm Hg of left ventricular end-diastolic pressure were obtained. Then the left circumflex coronary branch was partially constricted as was done in protocol I. After the hemodynamic steady state was attained, the Rp value was changed from 5.2 X lo3 to 9.5 X lo3 dynes.pcm-5. Because the change in Rp decreased cardiac output by approximately 40%, the left ventricular end-diastolic pressure was elevated from 6.5 f 0.7 to 14.5 f 1.3 mm Hg so that the cardiac output recovered the 40% decrease. Data 10 minutes after elevation of both Rp and left ventricular end-diastolic pressure were obtained. All measurements were performed within a period of 80 minutes, and there were no large changes (less than 10% of control) in hemodynamics and other variables tested during this time period.
All values of variables measured were expressed as mean f standard error of the mean. Statistical analysis of differences between the mean values at a given Rp and at a control resistance was performed with an analysis of variance and the Scheffe multiple comparison test. The unpaired Student t test was used for comparisons between the mean values in the preparations without and with coronary stenosis at the same Rp. Linear regression analysis was performed by a least-squares method. RESULTS Effect of afterload
elevation
with
constant
preload:
Figure 2 shows global left ventricular and coronary hemodynamics. In the preparations without coronary stenosis, peak left ventricular pressure increased from 140 f 4.1 to 156 f 3.8 mm Hg at 5.1 X lo3 dyne+*cmV5 of peripheral resistance (p <0.05), and to 167 f 3.5 mm Hg atRp= 10.7 X lo3 dynes+cmm5 (p
(Support
Dog/
Pump
FKURE 1. The experimental setup. The isolated heart is Ioaded with a hydraulic system simulating the aortic input impedance of the dog. A large va~able-he~gbt reservoir of saline solution is connected to the left atrium through the pulmonary vein. The heart is perfused with the arterial blood from the support dog by a servo-controlled peristaltic pump. The weight of ventricular muscle perfused by the left anterior descending and left circumflex branches, which was determined using indocyanine green, was 66 f 9.6 and 37 f 6.2 g in protocol I and 55 k 5.7 and 35 X! 5.6 g in protocol II, respectively. See text for details. Rc = characteristic resistance; Rp =
THE AMERICAN
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Rp(x103dyneSseccrE5)
6
-
8
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of afterload
elevation
combined
with
preload
After the mean left circumflex coronary flow was reduced by stenosis from 58 f 7.6 to 20 f 3.6 ml/ min, peak left ventricular pressure decreased significantly (126 f 2.9 vs 100 f 4.4 mm Hg, p
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PlGURE 2. Relation between the peripheral resistance (Rp) and the hemedynamics in 8 hearts in protocol I (afterload elevation with constant preload). Values are mean f standard error of the mean. AoP = mean aortic pressure; CO = cardiac output; LVP = peak left ventricular pressure; Cor Fme = mean bleed flow of the left anterior descending branch; CorLcx = mean blood flow of the left circumflex branch. tp <0.05; ftp
DISCUSSION Effects of aflerload on the ischemic myocardium: We recently reported the effects of afterload reduction on ischemic myocardial function in a preparation with coronary stenosis under the conditions of constant preload and constant heart rate.7,8J1 However, the effect of aortic pressure elevation alone on the ischemic myocardium is not yet clear.4-6 This difficulty may relate to simultaneous changes in preload or heart rate, or both, during the afterload elevation intervention, as previously described. In addition, differences in size of the ischemic area must be taken into account, when considering previous conflicting studies. 4-6 If the increased coronary blood flow is sufficiently offset by increased left ventricular end-diastolic pressure through a large size of -ischemia, then regional function would decrease with increased afterload. Moreover, systolic shortening of the ischemic myocardium at constant preload depends not only on contractility but also on afterload pressure. Accordingly, the systolic mechanical function of the ischemic myocardium may not be estimated if the afterload-systolic shortening relation in the nonischemic and ischemic myocardium are not compared with each other; otherwise different conclusions may emerge. In our study, systolic shortening of the ischemic myocardium decreased only slightly with the elevation of afterload-the load dependency of the ischemic myocardium was less than that of the nonischemic myocardium. The small dependency on afterload may be a result of alleviation of ischemia produced by an increase in blood flow of the partially constricted coronary artery at high aortic pressure. When preload changes occur during the intervention, systolic shortening is also affected by such changes, as well as changes in contractility and afterload. Therefore, in order to determine how the ischemic myocardium responds to afterload elevation with and without preload increase, it is not reasonable to directly compare the magnitudes of systolic shortening in the ischemic area obtained in protocols I and II. From this point of view, as
TABLE I Regional Myocardiai with Constant Preload)
LCX region
SS (mm) (“lo ss of control) EDL ST deviation (mV. n = 7) PmCO’ (mm Hg)
* p 10.01; t p <0.05 compared with that at the same peripheral resistance All values are mean f standard error EDL = end-diastok segment length; systolic shortening.
Function
Without
1.48 f 0.23 (100)
and With Stenosis
1.31 f0.20
of the Left Circumflex
0.97 f 0.18
Branch
1.02f0.14
10.00
(67 f 6)* 10.07 f 0.07
(72 f 6)z 10.22 * 0.07
0
0.39 * 0.14
0.52&0.18
3.12&0.76*
41 f 2.8
39 f 2.4
I (Afterload
Elevation
0.94 f 0.09
(83 f 1)+ 9.96 f 0.07
41 f 2.3
in Protocol
o.83*oo.11
(67 f 9)s 10.07 f 0.07 2.47 f 0.481
(61 f 6) 10.11 f 0.12 0.97 f 0.54+
53 Tk 2.15
47 f 0.8*5
60 f 3.9*
that at a peripheral resistance of 4.1 X 103 dynes. s. WI-~ in hearts without and with coronary stenosis; * p
shown in the results of protocol II (Table II), the ischemic region did not show the small load dependency that was found in protocol I, since the systolic shortening change was similar in both the nonischemic and ischemic myocardium. In this study, myocardial CO2 tension, elevated by partial stenosis, decreased linearly with the elevation of aortic pressure under constant preload. This was in agreement with the results of Wyatt et al5 obtained from lactate measurements. The alleviation of ischemia by afterload elevation with constant preload was also evidenced by the decrease in ST-segment deviation of the epicardial electrocardiogram in the ischemic region. Additionally, the cancellation effect of preload elevation was again observed. These results are in line with our previous study.12 The reason why preload increase deteriorates ischemic injury is unclear. In the presence of 50% flow reduction of the left anterior descending coronary artery, Grover and Weiss13 found no change in the oxygen supply consumption balance in the ischemic region during preload elevation accompanied with afterload elevation. However, it is probable that decreased myocardial blood flow in the inner layer of the myocardium is induced14 and that even increased coronary blood flow measured with an electromagnetic flowmeter is not enough to satisfy the augmented oxygen demand due to increased wall tension; as a result, these effects may lead to further deterioration of myocardial ischemic injury after preload elevation. The results of our study are of limited applicability in the clinical situation since the extent of the ischemic area, development of collateral circulation and severity of ischemia vary from patient to patient. However, our data may provide important principles regarding afterload alteration in the treatment of patients with coronary stenosis.
with SS =
I
I
TABLE II Regional Protocol II (Afterload Elevation)
Myocardial Elevation Without Stenosis ___
Rp (X lo3 dynes. s. cme5)
,-YLln
SS (mm) (% SS of control)
region
EDL (mm)
LCX region
(mv)
SS (mm) (% SS of control) EDL (mm) ST deviation (mv) PmCOz (mm Hg)
* p 10.01
compared
with
of Five Hearts with Preload
With Stenosis
5.2
LVEDP (mm Hg)
ST deviation
Function Combined
5.2
in
9.5
6.2 f 0.9
6.4 i 0.8
1.56 f 0.17
1.59 f 0.21 (102 f 5) 10.23 f 0.13 2.15*0.73+
1.42 f 0.22 (89 f 6) 10.65f 0.53* 1.40f0.71
0.86 f 0.44 (65 f 13)
0.79 f 0.26 (55* 11)
(100) 10.00
0 1.28zk0.21 (100)
10.00 0 4of the value
14.0
10.12f0.16 2.1 before
ll.OOf0.12”
3.00f0.94+ 54 f 2.2* afterload
f 1.43
2.65 f 1.13 53 f 2.8
elevation
All values are mean f standard error of the mean. LEVDP = left ventricular end-diastolic pressure. Other abbreviations
combined
with
are as in Table
I
I
EKERENCES 1. Kburi SF, Kloner RA, Hillis D, Tow DE, Barsamian EM, Maroko PR, Braunwald E. Intramural PCO2: a reliable index of the severity of myocardial ischemic injury. Am J Physiol 1979;237:H253-8259. ;2. Watanabe T, Cove11 JW, Maroko PR, Braunwald E, Ross J Jr. Effects of increased arterial pressure and positive inotropic agents on the severity of myocardial ischemia in the acutely depressed heart. Am J Car&d 1972;3@371-377. 3. Hillis LD, Izquierdo, Davis C, Brotherton S, Eberhart R, Roan PG, Wilerson JT. Effect of various degrees of systemic arterial hypertension on acute canine myocardial &hernia. Am J Physiol 198f;24O:H855-H861, 4. Lekven J, Kiil F. Myocardial function in general and regional left ventricular ischemia in dogs at control and high aortic blood-pressure. Car&wax Res 1975;9:373-383. 5. Wyatt HL, da Luz PL, Waters DD, Swan HJC, Forrester JS. Contrasting influences of alterations in ventricular preload and afterload upon systemic hemodynamic function and metabolism of ischemic myocardium. CircAfion 1977;55: 318-324.
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6. Sasayama S, Osakada G, Takahashi M, Shimada T, Kawai C. Modification of regional function of ischemic myocardium by the alteration of arterial pressure in dog. Cardiouasc Res 198O:I 4:93-I 02. 7. Isoyama S, Maruyama Y, Ashikawa K, Sato S, Suzuki H, Watanabe J, Shimizu Y, Ino-Oka E, Takishima T. Effects of afterload reduction on global left ventricular and regional myocardial functions in the isolated canine heart with stenosis of a coronary arterial branch. Circulation 1983,67:139-147. 6. Isoyama S, Maruyama Y, Koiwa Y, Ishide N, Kitaoka S, Tam&i K, Sato S, Shimizu Y, Ino-Oka E, Takishima T. Experimental study of afterload reducing therapy. The effect of the reduction of systemic vascular resistance on cardiac output, aortic pressure and coronary circulation in isolated, ejected canine hearts. Circulation 1981;64:490-499. 9. Watanabe J, Maruyama Y, Ashikawa K, Isoyama S, Satoh S, Suzuki H, Shimizu Y, Ino-Oka E, Takishima T. The changes in ECG ST segment and mechanical function of regional ischemic myocardium during afterload reduction in isolated dog hearts with coronary stenosis. Jpn Circ J 1986;50:248-257. 10. Esashi M, Matsuo T. Integrated micro multi ion sensor using field effect of
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semiconductor. Biomedical Eng 1978;25:184-192. 11. Maruyama Y, Ashikawa K, Isoyama S, Satoh S, Suzuki H, Watanabe J, Shimizu Y, Ino-Oka E, Takishima T. Pressure-length loop in the ischemic segment during left circumflex coronary artery stenosis and its modification by afterload reduction in excised perfused canine hearts. Basic Res Cardiol 1984;79:155-163. 12. Satoh S, Maruyama Y, Ashikawa K, Isoyama S, Suzuki H, Watanabe J, Nishioka 0, Ino-Oka E, Takishima T. Effects of preload alteration on the degree of ischemia and function of ischemic myocardium under constant mean aortic pressure, coronary perfusion pressure and heart rate in isolated perfused canine hearts. Jpn Circ J 1986;50:1100-1112. 13. Grover GJ, Weiss HR. Effect of aortic constriction-on the oxygen supplyconsumption balance in partially ischemic myocardium. Cardiouasc Res 1986;
20:498-503. 14. Kjekshus cardium
499.
during
JK. Mechanism for flow distribution in normal and ischemic myoincreased ventricular preload in the dog. Circ Res 1973;33:489-
The effect of afterload elevation on the ischemic myocardium was examined in an isolated, paced canine heart with a partial coronary stenosis. The coronary blood flow of the left circumflex coronary artery was reduced to approximately one-third of the values before stenosis. The left circumflex coronary stenosis produced a decrease in global ventricular function, a decrease in systolic shortening and deviation of the ST-segment of the epicardial electrocardiogram,and an increase in myocardial carbon dioxide (CO4 tension of the ischemic region. Then, afterload elevation with constant preload decreased the myocardial CO2 tension and improved the ST-segment deviation of the ischemic myocardium. Mechanical function, estimated by the relation between mean aortic pressure and systolic shortening, also improved with elevation of mean aortic pressure. In contrast, afterload elevation combined with preload elevation did not improve ischemic injury, as estimated by myocardial CO2 tension, and did not improve ST-segment deviation or mechanical function despite an increase in left circumflex coronary flow. These results suggest that the elevation of afterload pressure under constant preload improves ischemia produced by a partial coronary stenosis due to increased coronary blood supply; however, the preload elevation counterbalances the beneficial effects of afterload elevation. (Am J Cardiol 1989;63:40E-44E)
From the First Department of Internal Medicine, Tohoku University School of Medicine, l-l Seiryo-machi, Sendai, 980 Japan. Address for reprints: Tamotsu Takishima, MD, First Department of Internal Medicine, Tohoku University School of Medicine, l-l Seiryo-machi, Sendai, 980 Japan.
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lthough it wasfound that reduction of aortic pressure leads to deterioration of the contractile function of the ischemic myocardium,’ whether elevation of aortic pressure decreases the severity of ischemia has not been fully elucidated. In prior studies,2,3 in which regional ischemia was produced by a complete occlusion of a coronary arterial branch, the elevation of aortic pressure was found to decrease the severity of ischemia except when the aortic pressure was extremely elevateda However, there have been only a few controversial reports4-6 of studies in a heart with an incomplete occlusion. In these studies, mechanical function of the ischemic myocardium was depressed,4 did not changes or was improved,6 and afterload elevation was accompanied by increases in preload and changes in heart rate.5 Accordingly, we attempted to clarify how the elevation of aortic pressure affects ischemic myocardial function under 2 conditions, i.e., first, afterload elevation with constant preload and second, afterload elevation combined with preload elevation. METHODS Surgical
preparation (Fig. 1): Procedures for surgical preparation have been described elsewhere.‘l Thirteen mongrel dogs weighing 13.6 to 18.0 kg (mean 15.1) were used. A Gregg-type cannula was inserted through the brachiocephalic artery to the ascending aorta. Just after starting coronary perfusion with arterial blood from a support dog, the heart was isolated. The cannula was then advanced into the ostium of the left common coronary artery. The adaptor of the hydraulic loading system7p8 was connected to the aorta. In this study, only the peripheral resistance (Rp) value was changed in a stepwise fashion. The mean perfusion pressure was maintained equal to the mean aortic pressure throughout each experiment, as was done in the previous study.7 Coagulation was prevented with heparin (10,000 U initial injection, and 5,000 U every hour thereafter). The hydrogen ion concentration, (pH), partial pressure of oxygen (PO& partial carbon dioxide pressure (PC03 and hemoglobin of the arterial blood of the support dog were maintained within a physiologic range, i.e., 7.37 to 7.51 for pH, 75 to 120 mm Hg for PO;?, and 10.0 to 16.0 g/d1 for hemoglobin. Measurements and calculations: Left ventricular, aortic and perfusion pressures, and aortic, mean left coro-
nary and mean left circumflex coronary blood flows were measured as described previously.7,s Mean coronary blood flow of the left anterior descending artery was calculated by subtracting the value of mean left circumflex coronary flow from mean left coronary flow value. Cardiac output was measured from the amount of saline solution ejected over 20 seconds. To measure regional dimensions, 2 pairs of miniature (1.5 to 2.0 mm in diameter) ultrasonic crystals were implanted subendocardially: 1 in the left circumflex segment in the center of the cyanotic area, and the other in the left anterior descending segment. End-diastolic and end-systolic dimensions were determined as previously performed.7 Systolic shortening was calculated as the difference between these 2 lengths. For electrocardiographic recordings, 2 epicardial electrodes were sutured at the surface of the left ventricle,9 near the ultrasonic crystals. The system for measuring myocardial CO2 tension at the subendocardial layer of the left ventricle has been described elsewhere.lO The linear range of the system was between 10 and 200 mm Hg of CO2 tension and the 90% response time was 45 seconds. Experimental protocols: In protocol 1, the effect on the ischemic myocardium of pure afterload elevation with constant preload was examined; in protocol II, we examined the effect on the ischemic myocardium of afterload elevation combined with preload elevation, since afterload elevation often accompanies preload elevation with only a slight decrease of cardiac output in the clinical situation. In protocol I (n = 8), at a constant left ventricular end-diastolic pressure (6.1 f 1.2 mm Hg) and heart rate (140 f 3 beats/min), the Rp was elevated from 4.1 X 1O3 to 5.3 X lo3 and to 10.7 X lo3 dynes-*cme5 in a stepwise fashion at intervals of 10 minutes. Then, at 4.1 X lo3 dynes+cme5 of Rp, the mean left circumflex coronary flow wasreduced to 33% of the control value (range 24 to 46%) with a screw-driven metal clamp. Ten minutes after stenosis of the left circumflex coronary branch, we observed that a steady-state of hemodynamics and myocardial CO:! tension had been reached. Thereafter, we elevated the value of Rp in the same manner and in the same intervals as previously described. In protocol II (n = 5), the prestenosis data at 5.2 X IO3 dynepscme5 of Rp and 6.5 f 0.7 mm Hg of left ventricular end-diastolic pressure were obtained. Then the left circumflex coronary branch was partially constricted as was done in protocol I. After the hemodynamic steady state was attained, the Rp value was changed from 5.2 X lo3 to 9.5 X lo3 dynes.pcm-5. Because the change in Rp decreased cardiac output by approximately 40%, the left ventricular end-diastolic pressure was elevated from 6.5 f 0.7 to 14.5 f 1.3 mm Hg so that the cardiac output recovered the 40% decrease. Data 10 minutes after elevation of both Rp and left ventricular end-diastolic pressure were obtained. All measurements were performed within a period of 80 minutes, and there were no large changes (less than 10% of control) in hemodynamics and other variables tested during this time period.
All values of variables measured were expressed as mean f standard error of the mean. Statistical analysis of differences between the mean values at a given Rp and at a control resistance was performed with an analysis of variance and the Scheffe multiple comparison test. The unpaired Student t test was used for comparisons between the mean values in the preparations without and with coronary stenosis at the same Rp. Linear regression analysis was performed by a least-squares method. RESULTS Effect of afterload
elevation
with
constant
preload:
Figure 2 shows global left ventricular and coronary hemodynamics. In the preparations without coronary stenosis, peak left ventricular pressure increased from 140 f 4.1 to 156 f 3.8 mm Hg at 5.1 X lo3 dyne+*cmV5 of peripheral resistance (p <0.05), and to 167 f 3.5 mm Hg atRp= 10.7 X lo3 dynes+cmm5 (p
(Support
Dog/
Pump
FKURE 1. The experimental setup. The isolated heart is Ioaded with a hydraulic system simulating the aortic input impedance of the dog. A large va~able-he~gbt reservoir of saline solution is connected to the left atrium through the pulmonary vein. The heart is perfused with the arterial blood from the support dog by a servo-controlled peristaltic pump. The weight of ventricular muscle perfused by the left anterior descending and left circumflex branches, which was determined using indocyanine green, was 66 f 9.6 and 37 f 6.2 g in protocol I and 55 k 5.7 and 35 X! 5.6 g in protocol II, respectively. See text for details. Rc = characteristic resistance; Rp =
THE AMERICAN
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MARCH
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A SYMPOSIUM:
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MYOCARDIAL
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Rp(x103dyneSseccrE5)
6
-
8
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of afterload
elevation
combined
with
preload
After the mean left circumflex coronary flow was reduced by stenosis from 58 f 7.6 to 20 f 3.6 ml/ min, peak left ventricular pressure decreased significantly (126 f 2.9 vs 100 f 4.4 mm Hg, p
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PlGURE 2. Relation between the peripheral resistance (Rp) and the hemedynamics in 8 hearts in protocol I (afterload elevation with constant preload). Values are mean f standard error of the mean. AoP = mean aortic pressure; CO = cardiac output; LVP = peak left ventricular pressure; Cor Fme = mean bleed flow of the left anterior descending branch; CorLcx = mean blood flow of the left circumflex branch. tp <0.05; ftp
DISCUSSION Effects of aflerload on the ischemic myocardium: We recently reported the effects of afterload reduction on ischemic myocardial function in a preparation with coronary stenosis under the conditions of constant preload and constant heart rate.7,8J1 However, the effect of aortic pressure elevation alone on the ischemic myocardium is not yet clear.4-6 This difficulty may relate to simultaneous changes in preload or heart rate, or both, during the afterload elevation intervention, as previously described. In addition, differences in size of the ischemic area must be taken into account, when considering previous conflicting studies. 4-6 If the increased coronary blood flow is sufficiently offset by increased left ventricular end-diastolic pressure through a large size of -ischemia, then regional function would decrease with increased afterload. Moreover, systolic shortening of the ischemic myocardium at constant preload depends not only on contractility but also on afterload pressure. Accordingly, the systolic mechanical function of the ischemic myocardium may not be estimated if the afterload-systolic shortening relation in the nonischemic and ischemic myocardium are not compared with each other; otherwise different conclusions may emerge. In our study, systolic shortening of the ischemic myocardium decreased only slightly with the elevation of afterload-the load dependency of the ischemic myocardium was less than that of the nonischemic myocardium. The small dependency on afterload may be a result of alleviation of ischemia produced by an increase in blood flow of the partially constricted coronary artery at high aortic pressure. When preload changes occur during the intervention, systolic shortening is also affected by such changes, as well as changes in contractility and afterload. Therefore, in order to determine how the ischemic myocardium responds to afterload elevation with and without preload increase, it is not reasonable to directly compare the magnitudes of systolic shortening in the ischemic area obtained in protocols I and II. From this point of view, as
TABLE I Regional Myocardiai with Constant Preload)
LCX region
SS (mm) (“lo ss of control) EDL ST deviation (mV. n = 7) PmCO’ (mm Hg)
* p 10.01; t p <0.05 compared with that at the same peripheral resistance All values are mean f standard error EDL = end-diastok segment length; systolic shortening.
Function
Without
1.48 f 0.23 (100)
and With Stenosis
1.31 f0.20
of the Left Circumflex
0.97 f 0.18
Branch
1.02f0.14
10.00
(67 f 6)* 10.07 f 0.07
(72 f 6)z 10.22 * 0.07
0
0.39 * 0.14
0.52&0.18
3.12&0.76*
41 f 2.8
39 f 2.4
I (Afterload
Elevation
0.94 f 0.09
(83 f 1)+ 9.96 f 0.07
41 f 2.3
in Protocol
o.83*oo.11
(67 f 9)s 10.07 f 0.07 2.47 f 0.481
(61 f 6) 10.11 f 0.12 0.97 f 0.54+
53 Tk 2.15
47 f 0.8*5
60 f 3.9*
that at a peripheral resistance of 4.1 X 103 dynes. s. WI-~ in hearts without and with coronary stenosis; * p
shown in the results of protocol II (Table II), the ischemic region did not show the small load dependency that was found in protocol I, since the systolic shortening change was similar in both the nonischemic and ischemic myocardium. In this study, myocardial CO2 tension, elevated by partial stenosis, decreased linearly with the elevation of aortic pressure under constant preload. This was in agreement with the results of Wyatt et al5 obtained from lactate measurements. The alleviation of ischemia by afterload elevation with constant preload was also evidenced by the decrease in ST-segment deviation of the epicardial electrocardiogram in the ischemic region. Additionally, the cancellation effect of preload elevation was again observed. These results are in line with our previous study.12 The reason why preload increase deteriorates ischemic injury is unclear. In the presence of 50% flow reduction of the left anterior descending coronary artery, Grover and Weiss13 found no change in the oxygen supply consumption balance in the ischemic region during preload elevation accompanied with afterload elevation. However, it is probable that decreased myocardial blood flow in the inner layer of the myocardium is induced14 and that even increased coronary blood flow measured with an electromagnetic flowmeter is not enough to satisfy the augmented oxygen demand due to increased wall tension; as a result, these effects may lead to further deterioration of myocardial ischemic injury after preload elevation. The results of our study are of limited applicability in the clinical situation since the extent of the ischemic area, development of collateral circulation and severity of ischemia vary from patient to patient. However, our data may provide important principles regarding afterload alteration in the treatment of patients with coronary stenosis.
with SS =
I
I
TABLE II Regional Protocol II (Afterload Elevation)
Myocardial Elevation Without Stenosis ___
Rp (X lo3 dynes. s. cme5)
,-YLln
SS (mm) (% SS of control)
region
EDL (mm)
LCX region
(mv)
SS (mm) (% SS of control) EDL (mm) ST deviation (mv) PmCOz (mm Hg)
* p 10.01
compared
with
of Five Hearts with Preload
With Stenosis
5.2
LVEDP (mm Hg)
ST deviation
Function Combined
5.2
in
9.5
6.2 f 0.9
6.4 i 0.8
1.56 f 0.17
1.59 f 0.21 (102 f 5) 10.23 f 0.13 2.15*0.73+
1.42 f 0.22 (89 f 6) 10.65f 0.53* 1.40f0.71
0.86 f 0.44 (65 f 13)
0.79 f 0.26 (55* 11)
(100) 10.00
0 1.28zk0.21 (100)
10.00 0 4of the value
14.0
10.12f0.16 2.1 before
ll.OOf0.12”
3.00f0.94+ 54 f 2.2* afterload
f 1.43
2.65 f 1.13 53 f 2.8
elevation
All values are mean f standard error of the mean. LEVDP = left ventricular end-diastolic pressure. Other abbreviations
combined
with
are as in Table
I
I
EKERENCES 1. Kburi SF, Kloner RA, Hillis D, Tow DE, Barsamian EM, Maroko PR, Braunwald E. Intramural PCO2: a reliable index of the severity of myocardial ischemic injury. Am J Physiol 1979;237:H253-8259. ;2. Watanabe T, Cove11 JW, Maroko PR, Braunwald E, Ross J Jr. Effects of increased arterial pressure and positive inotropic agents on the severity of myocardial ischemia in the acutely depressed heart. Am J Car&d 1972;3@371-377. 3. Hillis LD, Izquierdo, Davis C, Brotherton S, Eberhart R, Roan PG, Wilerson JT. Effect of various degrees of systemic arterial hypertension on acute canine myocardial &hernia. Am J Physiol 198f;24O:H855-H861, 4. Lekven J, Kiil F. Myocardial function in general and regional left ventricular ischemia in dogs at control and high aortic blood-pressure. Car&wax Res 1975;9:373-383. 5. Wyatt HL, da Luz PL, Waters DD, Swan HJC, Forrester JS. Contrasting influences of alterations in ventricular preload and afterload upon systemic hemodynamic function and metabolism of ischemic myocardium. CircAfion 1977;55: 318-324.
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