Arbutamine stimulation detects viable myocardium 4 weeks after coronary occlusion

Arbutamine Stimulation Detects Viable Myocardium 4 Weeks After Coronary Occlusion Akira Kisanuki, MD, Douglas S. Segar, MD, Thomas Ryan, MD, Michael Johnson, Chuwa Tei, MD, Harvey Feigenbaum, MD, and Stephen G. Sawada, MD, Indianapolis, Indiana, and Kagoshima, Japan

At low doses, dobutamine has potent inotropic, but limited chronotropic, effects—properties that may be necessary for detection of hibernating myocardium. The efficacy of other catecholamines, which have more closely coupled inotropic and chronotropic effects, for the detection of viable myocardium is unknown. This study evaluated the efficacy of arbutamine, a catecholamine with potent chrono-tropic effects, for the detection of viable myocardium in a canine model of hibernating myocardium. Contractile reserve was assessed during stepwise arbutamine infusion (dosages of 2.5, 5, 10, 50, and 100 ng/kg/min) at 3 days (early) and 4 weeks (late) after coronary ligation. Segment shortening, wall thickening, and segmental wall motion were assessed by sonomicrometry and echocardiography. After 4 weeks of occlusion, functional recovery was assessed after revascularization. During the early arbutamine study, the sensitivity for predicting functional recovery was

The detection of viable myocardium is an issue of increasing importance in the management of patients with reduced left ventricular function.The presence of viable myocardium identifies those patients who

From the Department of Medicine of Indiana University School of Medicine, Krannert Institute of Cardiology, Roudebush Veterans Affairs Medical Center, and Wishard Memorial Hospital, Indianapolis, Ind, and from the First Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Japan (A.K., C.T.). Dr Ryan’s current position is with Duke University Medical Center, Durham, NC. This study was supported by the Herman C. Krannert Fund, Indianapolis, Ind; grants HL-06308 and HL-07182 from the National Institutes of Health, Bethesda, Md; and Gensia, Inc, San Diego, Calif. This study was presented in part at the Scientific Sessions of the American Heart Association in New Orleans, La, Oct 1996. Reprint requests: Stephen Sawada, MD, Krannert Institute of Cardiology, 1111 West Tenth Street, Indianapolis, IN 46202. Copyright © 2001 by the American Society of Echocardiography. 0894-7317/2001/$35.00 + 0 27/1/108932 doi:10.1067/mje.2001.108932

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highest at a dosage of 50 ng/kg/min, which also produced tachycardia. The sensitivity was 50% for segment shortening, 20% for wall thickening, and 75% for wall motion score. The late arbutamine study had improved sensitivity. The sensitivity was 100% for segment shortening, 80% for wall thickening, and 90% for wall motion score at a dosage of 50 ng/kg/ min. At the late arbutamine study, myocardial perfusion reserve in the ischemic zone of dogs with functional recovery was only mildly reduced (2.0 versus 2.6 in nonischemic zones, P = .53). After coronary occlusion, viable myocardium can be detected with high doses of arbutamine that produce tachycardia. However, the sensitivity of arbutamine stimulation for predicting functional recovery is low early after occlusion, but it is improved by 4 weeks after occlusion with adequate perfusion reserve. (J Am Soc Echocardiogr 2001;14:138-48.)

have an improvement in systolic function and survival with revascularization.1-4 The results of recent studies suggest that assessment of contractile reserve with dobutamine echocardiography is a clinically useful method for identifying viable myocardium.2,5-8 At low doses, dobutamine has significant inotropic effects but weaker chronotropic effects.9 The results of animal studies suggest that these properties contribute to the sensitivity for the detection of viable myocardium when severe coronary artery disease is present.10,11 The results of human studies suggest that the sensitivity of dobutamine stimulation for the prediction of functional recovery of stunned or hibernating myocardium may decrease when higher doses that produce tachycardia are administered.12,13 In the setting of limited myocardial perfusion reserve, tachycardia may upset the tenuous balance between myocardial oxygen supply and demand and may limit the contractile response of viable myocardium. In contrast to dobutamine, other catecholamines such as isoproterenol and epinephrine that have been used for stress testing purposes have more

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potent chronotropic effects and more closely coupled inotropic and chronotropic potency.9,14-17 Little is known about the efficacy of these agents for detection of viability. In theory, the ability of these agents to produce tachycardia might limit their sensitivity for detection of viable myocardium in the setting of severe coronary artery disease with reduced myocardial perfusion. Arbutamine is a new catecholamine that was developed as a stress testing agent.18-22 Arbutamine has a chronotropic potency more similar to isoproterenol than to dobutamine and has more closely coupled inotropic and chronotropic effects compared with dobutamine.18-20 Arbutamine also has less inotropic activity compared with dobutamine.18 In this study, we sought to determine whether catecholamines with potent chronotropic effects are useful for the detection of viable myocardium by testing the efficacy of arbutamine in an animal model of hibernating myocardium. In such a model, we have previously shown that dobutamine stimulation has good sensitivity for the detection of viable myocardium both early and late after coronary occlusion.23 We hypothesize that if the same holds true for arbutamine, the uncoupling of inotropic and chronotropic potency is not required for detection of viability with the use of catecholamine stimulation.

METHODS The study was approved by the Indiana University School of Medicine Animal Care Committee, and all experiments were conducted in accordance with its guidelines for humane treatment of laboratory animals. Study Design Mongrel dogs underwent coronary occlusion, which was maintained for 4 weeks, followed by revascularization. Arbutamine studies were performed 3 days (early) and 4 weeks (late) after occlusion before revascularization. Segment shortening, wall thickening, and regional wall motion were assessed before and after occlusion, during each arbutamine infusion, and after revascularization. Animal Preparation Eleven mongrel dogs were used for the study. Each dog was intubated with an endotracheal tube after initial sedation with intravenous sodium thiopental (25 mg/kg). Each dog was then fully anesthetized with isoflurane (100% oxygen, 1.0 to 1.75 vol/100 mL isoflurane) and mechanically ventilated with a standard veterinary respirator. Under sterile conditions, a left thoracotomy was performed in the fourth or fifth intercostal space, and the heart was exposed. Pairs of 1.5-mm, 5-MHz sonomicrometer crystals

Kisanuki et al 139

were implanted in the subendocardial layer of the myocardium supplied by the left anterior descending coronary artery (ischemic zone), and in the myocardium supplied by the left circumflex coronary artery (nonischemic zone). Each crystal wire was attached by a suture to the epicardial surface to avoid dislocation at the site of their epicardial exit. Baseline measurements of segment shortening were then performed. Long- and short-axis 2-dimensional echocardiographic views of the left ventricle were obtained with a 5.0-MHz transducer (ATL UM 4, Bothell, Wash) placed at the right chest wall.The images were digitized on-line (Microsonics PreView, Mahwah, NJ) and recorded on VHS videotape. After baseline echocardiographic and sonomicrometric examinations were performed, the proximal left anterior descending coronary artery was ligated with a silk tie.The examinations were repeated, and the chest was closed. Additional echocardiographic images and segment shortening data were obtained 1 hour after coronary artery ligation.The dogs received buprenorphine (0.02 mg/kg) for 2 days, penicillin G (200,000 U) on the day of the operation, and cefazolin (2 g/day) for 3 days postoperatively. Arbutamine Studies Each dog underwent intravenous infusion of arbutamine and had assessment of segment shortening, wall thickening, and wall motion at day 3 (early) and at 4 weeks (late) after the initial operation.With use of the procedures previously described, dogs were fully anesthetized during the arbutamine studies. Arbutamine was infused at dosages of 2.5, 5, 10, 50, and 100 ng/kg/min, and the infusion was increased every 6 minutes.The drug was delivered through an antebrachial vein by a preprogrammed injection device. Hemodynamic Assessment and Revascularization at 4 Weeks After induction of anesthesia, a femoral artery catheter was placed for pressure measurement and blood withdrawal, and a femoral vein catheter was placed for administration of medications.The arterial pressure line was connected to a domed pressure transducer and calibrated to a mercury manometer.The left chest wall was opened. Left ventricular pressure was monitored by using a micromanometertipped catheter inserted into the left ventricle via a stab incision in the left atrial appendage.The rate of change of left ventricular pressure (dP/dt) was obtained via a differentiating circuit. Through a separate stab incision in the left atrial appendage, a catheter was placed into the left atrium for radio-labeled microsphere injection. Standard needle electrodes were placed subcutaneously for electrocardiographic recording. The late arbutamine study was performed as previously described. Echocardiographic images, sonomicrometric measurements, and left ventricular pressure were record-

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ed. Fifty µCi of 15 µm microspheres (New England Nuclear) labeled with cobalt-51, tin-113, ruthenium-103, or niobium-95 were injected into the left atrium at baseline and at a dosage of 100 ng/kg/min of arbutamine to measure myocardial blood flow (MBF). Reference blood samples were withdrawn from the femoral artery at a rate of 8 mL/min beginning 30 seconds before injection and continuing for 90 seconds after injection. Coronary artery bypass grafting from the right carotid artery to a site distal to the ligation of the left anterior descending coronary artery was performed with use of a cannula connected to a roller pump. The coronary flow was maintained for 1 hour at a rate of 7.5 to 12.0 mL/min. Echocardiographic and sonomicrometric examinations were performed 60 minutes after revascularization. Sonomicrometric Measurements Sonomicrometric crystals were connected to a 4-channel sonomicrometer module. Sonomicrometer data, left ventricular pressure, and electrocardiographic signals were recorded on an 8-channel recorder on 50-mm/s strip charts.The same data were analyzed with use of an on-line computer system (Apple Macintosh IIFx, Apple Computer Inc, Cupertino, Calif; LabView Runtime software, National Instruments,Austin,Tex). Segment shortening was calculated in the ischemic zone of each animal by using the formula End-diastolic segment length – End-systolic segment length / End-diastolic segment length × 100%. Wall Thickening Analysis One investigator measured myocardial thickening at the center of the ischemic zone from short-axis images recorded on videotape.This ischemic zone was identified by the presence of wall motion abnormalities after coronary occlusion. The short-axis plane with echoes produced by the sonomicrometer crystals was used for measurement. The papillary muscles were used as landmarks to ensure that measurements were performed at the same location of the short-axis images during the arbutamine studies and after revascularization. Myocardial thickness was measured from the endocardium to the epicardium with a computerized light pen in end diastole and in end systole. Myocardial thickening was defined as (End-systolic thickness – End-diastolic thickness / End-diastolic thickness) × 100%. The reported values represent a mean of 3 consecutive cardiac cycles. Intraobserver reproducibility was assessed with 64 repeated measurements of wall thickening. The average difference between initial and repeated measurements was 1% ± 5.4%. The measurement error according to Bland and Altman was 11.8%.24 Wall Motion Analysis Left ventricular wall motion analysis was performed by an investigator who reviewed the digitized images.Videotaped

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recordings were reviewed if the captured images were inadequate.The left ventricle was divided into 16 segments by using the long-axis and short-axis views at the basal, midpapillary muscle, and apical levels. A semiquantitative scoring system for wall motion (1 = normal, 2 = hypokinesis, 2.5 = severe hypokinesis, 3 = akinesis, 4 = dyskinesis) was used as previously described.25 Hyperkinesis, above normal contractility with arbutamine,was scored as 0.5.For each dog, the ischemic zone was defined as the segments with wall motion abnormalities after coronary artery ligation at the initial surgery. Assessment for Functional Recovery In the ischemic zone, significant improvement during arbutamine infusion and functional recovery with revascularization were defined as a >5% increase in segment shortening and a >12% increase in wall thickening (average difference of repeated measurements ±2 SD).26 For ischemic zone segments with abnormal wall motion, significant improvement with arbutamine and functional recovery were defined by a >0.5 decrease in wall motion score. Blood Flow Analysis Sliced myocardial tissue samples (approximately 1 cm3) were obtained from the ischemic and nonischemic zones and placed in tubes for weighing.Tissue and reference blood samples were counted in a gamma scintillation counter (Hewlett-Packard series 5000 multichannel analyzer, Andover, Mass) at the respective energies for each isotope. Counts emitted from the different isotopes were separated by a spectral stripping technique to calculate specific activity over the time periods. Regional MBF was obtained by using the following equation: MBF = (Ct/TW) × (RBW/Cb) × 100, where MBF = MBF in mL/min per 100gram tissue, Ct = tissue radioactive counts, TW = tissue weight in grams, RBW = reference blood withdrawal rate in mL/min, and Cb = total radioactive counts of the reference blood sample. Regional MBF in the ischemic and nonischemic zones was determined by the mean of 3 samples from each zone. Perfusion reserve (MBF at a dosage of 100 ng/kg/min divided by MBF at baseline) was determined in ischemic and nonischemic zones. Statistical Analysis Group data are reported as mean values ± SD. One-way analysis of variance was used to analyze changes in hemodynamics and blood flow data. Repeated-measures analysis of variance was used to analyze changes in segment shortening, myocardial thickening, and wall motion score before and after occlusion, during the arbutamine studies, and after revascularization.An interaction term with P < .05 denotes significant differences between groups in the response to occlusion, revascularization, or arbutamine.The paired t test was used to analyze the changes of these 3 indexes at base-

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A

B

Figure 1 Comparison of segment shortening between the group with functional recovery (FR) and the group without functional recovery (No FR) during the early (A) and late (B) arbutamine studies. During the early arbutamine study, no significant differences in segment shortening were seen between groups with and without functional recovery. During the late arbutamine study, significant improvement in segment shortening was seen in the functional recovery group compared with segment shortening in the group without functional recovery (P = .011). BL, Baseline.

Table 1 Hemodynamic changes during the early and late arbutamine studies Arbutamine (ng/kg/min) BL

Early arbutamine study: HR (bpm) Late arbutamine study: HR (bpm) SLVP (mm Hg) DLVP (mm Hg) dP/dt (mm Hg/s, × 102) RPP (× 103)

99 103 82 9 11.1 8.6

± ± ± ± ± ±

2.5

17 15 21 4 3.9 2.7

97 113 109 11 17.4 12.3

± ± ± ± ± ±

14 12 20 3 2.9* 2.2

5.0

96 117 112 12 17.1 13.3

± ± ± ± ± ±

14 13 26 2 2.2* 3.7

10

105 122 110 10 17.7 13.5

± ± ± ± ± ±

17 15* 26 2 1.8* 4.3

50

143 141 118 11 25.7 16.7

± ± ± ± ± ±

19* 24* 37* 3 4.6* 5.6*

100

150 151 150 12 29.2 22.8

± ± ± ± ± ±

20* 26 45* 3 2.3* 7.7*†

BL, Baseline; D, end-diastolic; HR, heart rate; DLVP, diastolic left ventricular pressure; RPP, rate pressure product; SLVP, systolic left ventricular pressure. *P < .05 versus BL. †P < .05 versus arbutamine 50.

line between early and late arbutamine studies.The sensitivity, specificity, and accuracy of arbutamine stimulation for predicting functional recovery after revascularization were determined. Segment shortening, wall thickening, and segmental wall motion during arbutamine stimulation and after revascularization were compared with use of linear regression. Statistical significance was defined as P < .05.

RESULTS Experimental Procedures Eleven dogs underwent coronary artery ligation. One dog died 4 days after ligation, one after 1 week, and

1 just before revascularization. Revascularization was successfully performed in the remaining 8 dogs. Segment Shortening, Wall Thickening, and Wall Motion Score with Occlusion and Revascularization Segment shortening, myocardial thickening, and wall motion score in the ischemic zone worsened after coronary ligation. Functional recovery after revascularization was observed in 4 of 8 dogs by assessment of segment shortening, and in 5 of 8 dogs by assessment of wall thickening. Fourteen of 43 segments that showed abnormal wall motion after ligation showed spontaneous functional recovery to normal

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142 Kisanuki et al

A

B

Figure 2 Comparison of myocardial thickening between the functional recovery group and the group without functional recovery during early (A) and late (B) arbutamine studies. A trend toward significant improvement of myocardial thickening was seen in the functional recovery group during the late arbutamine study. FR, Group with functional recovery; No FR, group without functional recovery; BL, baseline.

wall motion by the time of the late arbutamine study. Functional recovery after revascularization occurred in 20 (69%) of 29 segments that showed abnormal wall motion at the time of the late arbutamine study before revascularization. Hemodynamics (Table 1) During the early arbutamine study, the first significant increase in heart rate occurred at a dosage of 50 ng/kg/min. During the late arbutamine study, the first significant increase in heart rate occurred at a dosage of 10 ng/kg/min. Rate pressure product was measured during the late arbutamine study.The first significant increase in rate pressure product occurred at 50 ng/kg/min, and the double product increased further at a dosage of 100 ng/kg/min. Changes in Regional Function with Arbutamine: Differences Between Early and Late Studies There was a significant decrease in the baseline wall motion score, both in segments that had functional recovery with revascularization (P = .0004) and in segments without functional recovery with revascularization (P = .03) from the time of the early to the late arbutamine study. During the early arbutamine study, no significant differences in segment shortening, myocardial thickening, or wall motion score were observed between the functional recovery group and the group without functional recovery (Figures 1, 2, and 3). During the late arbutamine

study, a greater increase in segment shortening was seen in the functional recovery group compared with the group without functional recovery (P = .011, Figure 1). During the late arbutamine study, a trend also existed toward a greater increase in myocardial thickening in the functional recovery group compared with the group without functional recovery (Figure 2). Finally, a significant decrease in wall motion score was found during the late study in segments with functional recovery compared with segments without recovery (P < .0001, Figure 3). Response to Arbutamine in Segments with Spontaneous Recovery of Function Fourteen segments with abnormal wall motion after occlusion had spontaneous recovery of function to normal by the time of the late arbutamine study. Four of these segments had regained normal function by the time of the early arbutamine study. The remaining 10 segments had abnormal wall motion at the time of the early arbutamine study. Nine of the 10 segments had improvement of wall motion with arbutamine at a dosage of 50 ng/kg/min.Therefore,the sensitivity of the early arbutamine study for prediction of spontaneous recovery of function before revascularization was 90%. Prediction of Wall Motion Improvement After Revascularization (Table 2) The sensitivity of the early arbutamine study for predicting functional recovery after revascularization was

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A

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B

Figure 3 Comparison of segmental wall motion score between segments with functional recovery and segments without functional recovery during the early (A) and late (B) arbutamine studies. Baseline wall motion score decreased from the early to the late arbutamine study in segments with functional recovery (**P = .0004) and in segments without recovery (†P = .03). During the early arbutamine study, no difference was seen in the changes in wall motion score between segments with functional recovery and those without recovery. During the late arbutamine study, a significant decrease was seen in wall motion score in segments with functional recovery compared with segments without recovery. FR, Group with functional recovery; No FR, group without functional recovery; BL, baseline.

50% for segment shortening, 20% for wall thickening, and 75% for wall motion score.These maximal sensitivities were achieved at a dosage of 50 ng/kg/min. The optimal sensitivity for predicting functional recovery of the late arbutamine study also occurred at a dosage of 50 ng/kg/min, reaching a maximum of 100% for segment shortening, 80% for myocardial thickening, and 90% for wall motion score.The sensitivities of segment shortening and myocardial thickening decreased at a dosage of 100 ng/kg/min compared with the values at a dosage of 50 ng/kg/min. The specificity and accuracy of the late arbutamine study were 75% and 88% for segment shortening, 100% and 88% for myocardial thickening, and 78% and 86% for wall motion score, respectively, at a dosage of 50 ng/kg/min. Correlation Between Segment Shortening, Myocardial Thickening, and Wall Motion Score After Revascularization and at 50 ng/Kg/min During the Late Arbutamine Study Significant positive linear relations were observed for values of segment shortening (r = 0.72, Figure 4), myocardial thickening (r = 0.95, Figure 5), and wall motion score (r = 0.65, Figure 6) obtained during the

late arbutamine study (dosage 50 ng/kg/min) and after revascularization. Myocardial Blood Flow During the Late Arbutamine Study Myocardial blood flow was significantly reduced in the ischemic zone in animals without functional recovery (40 ± 28 mL/min per 100 g) compared with that in nonischemic zones (107 ± 45 mL/min per 100 g) (P = .02). Myocardial blood flow was less severely reduced in the ischemic zone of animals with functional recovery (67 ± 42 mL/min per 100 g) compared with that in nonischemic zones (P = .16). Myocardial perfusion reserve was slightly reduced in ischemic zones with functional recovery (2.0 ± 1.6) compared with perfusion reserve in nonischemic zones (2.6 ± 1.3) (P = .53). DISCUSSION Animal Model of Chronic Left Ventricular Dysfunction In our study, about one third of segments that had abnormal wall motion at rest after coronary occlu-

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Table 2 Prediction of functional recovery after revascularization with use of the early and late arbutamine studies Arbutamine (ng/kg/min) 2.5

Early arbutamine study S-S sen (%) S-S spe (%) S-S acc (%) M-Th sen (%) M-Th spe (%) M-Th acc (%) WMS sen (%) WMS spe (%) WMS acc (%) Late arbutamine study S-S sen (%) S-S spe (%) S-S acc (%) M-Th sen (%) M-Th spe (%) M-Th acc (%) WMS sen(%) WMS spe (%) WMS acc (%)

5.0

10

50

100

0 100 43 20 100 50 5 100 34

(0/4) (3/3) (3/7) (1/5) (3/3) (4/8) (1/20) (9/9) (10/29)

0 67 29 0 100 38 10 89 34

(0/4) (2/3) (2/7) (0/5) (3/3) (3/8) (2/20) (8/9) (10/29)

0 67 29 20 100 50 35 78 48

(0/4) (2/3) (2/7) (1/5) (3/3) (4/8) (7/20) (7/9) (14/29)

50 67 57 20 100 50 75 56 69

(2/4) (2/3) (4/7) (1/5) (3/3) (4/8) (15/20) (5/9) (20/29)

50 67 57 20 100 50 75 56 69

(2/4) (2/3) (4/7) (1/5) (3/3) (4/8) (15/20) (5/9) (20/29)

0 100 50 0 100 38 10 78 31

(0/4) (4/4) (4/8) (0/5) (3/3) (3/8) (2/20) (7/9) (9/29)

0 100 50 0 100 38 35 78 48

(0/4) (4/4) (4/8) (0/5) (3/3) (3/8) (7/20) (7/9) (14/29)

25 100 63 20 100 50 65 78 69

(1/4) (4/4) (5/8) (1/5) (3/3) (4/8) (13/20) (7/9) (20/29)

100 75 88 80 100 88 90 78 86

(4/4) (3/4) (7/8) (4/5) (3/3) (7/8) (18/20) (7/9) (25/29)

75 75 88 40 100 63 90 78 86

(3/4) (3/4) (7/8) (2/5) (3/3) (5/8) (18/20) (7/9) (25/29)

Acc, Accuracy; M-Th, myocardial thickening; sen, sensitivity; spe, specificity; S-S, segment shortening; WMS, wall motion score.

sion had improvement to normal baseline wall motion by the time of the late arbutamine study. The spontaneous improvement of function suggests that myocardial stunning accounted for some of the initial depression in regional function manifested early after occlusion. However, regional function in most segments of each ischemic zone remained depressed at the end of 4 weeks of coronary occlusion, and restoration of function in these regions occurred only after revascularization. This persistent but reversible dysfunction may be attributed to hibernation. In hibernation, myocardial contractility is proportionately reduced to match the reduction in myocardial perfusion. In our study, perfusion in the ischemic zone in animals with functional recovery was modestly reduced compared with the flow in nonischemic zones (67 versus 107 mL/min/kg). Some of this reduction in flow could have been the result of nontransmural infarction, but the occurrence of functional recovery suggests that infarction, if present, was limited. In addition, flow in the ischemic zones of animals with functional recovery (67 mL/min/kg) was not as severely reduced as flow in the ischemic zones of animals without functional recovery (40 mL/min/kg) and presumed transmural infarction. Although the persistent ventricular dysfunction produced in this study may not be due to hibernation alone, it may be representative of the condition observed in human beings.The results of recent stud-

ies suggest that chronic dysfunction of viable myocardium represents a mixture of processes, including nontransmural infarction and repetitive stunning (with normal perfusion at rest), in addition to hibernation with reduced perfusion.25,27-32 On this basis, we expect that the animal model used in this study approximates the condition of chronic ventricular dysfunction in human beings. Efficacy of Early Versus Late Arbutamine Stimulation for Prediction of Functional Recovery Arbutamine is a catecholamine with potent chronotropic effects that are more similar to those of isoproterenol than to those of dobutamine.18 At low doses, arbutamine has relatively less potent inotropic effects compared with dobutamine, and more closely coupled inotropic and chronotropic potency, which is similar to isoproterenol. In theory, these properties of arbutamine may diminish the sensitivity of this and similar catecholamines for the detection of viable myocardium.18,19 Both the frequency and magnitude of the response of viable myocardium to inotropic stimulation may be limited when coronary perfusion is reduced and perfusion reserve is reduced or absent.10,11,33 In this setting, the propensity of some catecholamines to produce tachycardia might result in ischemia with failure to augment function in viable myocardium. In our study, arbutamine stimulation per-

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Figure 4 Segment shortening after revascularization (bypass) and during the 50-ng/kg/min stage of the late arbutamine study. SEE, Standard error of the estimate.

formed early after coronary occlusion had good sensitivity for the prediction of spontaneous functional recovery of presumably stunned segments,but limited sensitivity for prediction of functional recovery of hibernating segments. The response to arbutamine stimulation in hibernating myocardium improved with increasing dosages up to 50 ng/kg/min. However, the sensitivity of segment shortening and wall thickening for functional recovery was still low. At this dosage, a significant increase in heart rate and rate pressure product was found, suggesting that an increase in myocardial oxygen consumption may have contributed to failure to respond to arbutamine. The reduced sensitivity of the early arbutamine study for detection of hibernating myocardium is in contrast to results that we previously obtained with dobutamine stimulation early after coronary occlusion.In the same animal model, dobutamine stimulation early after occlusion identified hibernating myocardium in all dogs that had functional recovery.23 Four weeks after coronary occlusion, the sensitivity of arbutamine stimulation for predicting functional recovery of hibernating myocardium was substantially improved. In addition, the magnitude of response to arbutamine predicted the magnitude of improvement in regional function observed after revascularization. At the time of the late arbutamine study, MBF and perfusion reserve were only modestly depressed in animals that were demonstrated to have functional recovery with revascularization. Gradual improvement of collateral blood supply to the ischemic zone may account for this observation. The finding that some segments, presumed to be stunned, had recovery of function before revascular-

Kisanuki et al 145

Figure 5 Myocardial thickening after revascularization (bypass) and during the 50-ng/kg/min stage of the late arbutamine study. SEE, Standard error of the estimate.

Figure 6 Wall motion score after revascularization (bypass) and during the 50-ng/kg/min stage of the late arbutamine study. SEE, Standard error of the estimate.

ization supplies additional, indirect evidence of improvement in collateral blood supply. Catecholamine Dosage Requirements for Contractile Response In contrast to the efficacy of low doses of dobutamine for detection of viable myocardium, high doses of arbutamine were required to maximize sensitivity. In both animal and human studies, low dosages of dobutamine (≤20 µg/kg/min) have been shown to produce marked and near maximal increases in wall thickening and motion in viable myocardium with no or only modest elevations of heart rate.19,34 Hammond and McKirnan19 showed that to produce comparable

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increases in wall thickening, arbutamine had to be administered in relatively high dosages (≥120 ng/kg/min) that also produced significant tachycardia (60% increase in heart rate over baseline). In our study, maximal sensitivity of the late arbutamine study was achieved at a dosage of 50 ng/kg/min, which produced an average increase in heart rate of 37%.These data indicate that the relatively lower inotropic potency of arbutamine necessitates the use of high doses for maximizing the detection of viable myocardium. As previously discussed, some animals with functional recovery may have had hibernating myocardium coexisting with limited nontransmural infarction. Higher doses of a catecholamine may be required for recruitment of viable myocardium in the setting of nontransmural infarction. Armstrong32 has hypothesized that the required dose of inotrope increases in proportion to the extent of necrotic myocardium. This hypothesis is supported by the observation that segments improving only with high-dose dobutamine commonly have perfusion and metabolic evidence of nontransmural damage.25 At the highest dosage of arbutamine, 100 ng/ kg/min, the sensitivity of wall thickening and segment shortening for functional recovery declined from values obtained at a dosage of 50 ng/kg/min (Table 2). Average values for wall thickening in animals with functional recovery also declined at 100 ng/kg/min. The decline in sensitivity and wall thickening was most likely the result of development of stress-induced ischemia at this dosage. Rate pressure product also was significantly increased at this dosage above levels achieved at 50 ng/kg/min. The observation of a biphasic response to arbutamine stimulation in regions with functional recovery is not unexpected. A biphasic response with infusion of increasing dosages of dobutamine has been found to have the highest positive predictive value for functional recovery with revascularization.8,13 Regions with biphasic responses are likely to have transmural viability and some limitation of perfusion reserve.11 Study Limitations The study population was small. According to our analysis of wall thickening, 5 animals were classified in the functional recovery group, whereas 4 animals were classified in this group by segment shortening. Although every attempt was made to measure wall thickening in the same location as the sonomicrometer crystals in the ischemic zone of each dog, some variability in the site of measurement occurred. It is likely that wall thickening was measured at a location peripheral to the center of the ischemic zone in

Journal of the American Society of Echocardiography February 2001

the animal that had functional recovery by wall thickening but not by sonomicrometry. Previous studies have shown that functional recovery of hibernating myocardium may be delayed for weeks to months after the procedure. 8,30 In this study, assessment for functional recovery was performed early after revascularization, which may have led to underestimation of the extent of functional recovery. The sensitivity of arbutamine stimulation for functional recovery would be lower if some segments had a delayed return of function. The speed of recovery of function after revascularization is influenced by the degree of structural alterations present in hibernating myocardium.35 These structural alterations may become more severe as the hibernating state is prolonged and may result in a more delayed recovery. In this study, the period of coronary occlusion was relatively short. The spontaneous recovery of function also suggests partial improvement of perfusion before revascularization. These factors may have limited the number of segments that would have had severe structural alterations and a delayed return of function. Previous studies have also shown that the majority of hibernating segments have rapid improvement of function after revascularization.5,30 Conclusion The clinical applicability of this investigation depends largely on how closely our animal model of ventricular dysfunction resembles that observed in human beings.The recognition that chronic dysfunction in some patients may be due to repetitive stunning with normal perfusion at rest suggests that arbutamine and catecholamines with similar properties may have some utility for the detection of viability in human beings. However, because of their lower inotropic potency compared with dobutamine, relatively higher doses of other catecholamines are needed to elicit a contractile response in viable myocardium. At these higher doses, catecholamines such as arbutamine and isoproterenol with closely coupled inotropic and chronotropic potency produce significant tachycardia.These agents appear to retain sensitivity for detection of viable myocardium if perfusion reserve is only mildly decreased. They also may be useful in the identification of stunned myocardium early after coronary occlusion. However, when perfusion or perfusion reserve is severely reduced, the sensitivity of non-dobutamine catecholamines for predicting functional recovery of hibernating

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myocardium appears diminished. In this setting, the uncoupling of inotropic and chronotropic potency that is unique to dobutamine is an essential requirement for the detection of viability.

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12.

We thank Amy Stewart for secretarial assistance. 13.

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