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Circulation. 1995;92:756-766

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(Circulation. 1995;92:756-766.)
© 1995 American Heart Association, Inc.

Articles

Incremental Doses of Dobutamine Induce a Biphasic Response in Dysfunctional Left Ventricular Regions Subtending Coronary Stenoses

Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993.

Chunguang Chen, MD; Li Li, MD; Liang Long Chen, MD; Jose V. Prada, MD; Ming Hui Chen, MD; John T. Fallon, MD, PhD; Arthur E. Weyman, MD; David Waters, MD; Linda Gillam, MD

From the Division of Cardiology, Hartford Hospital, University of Connecticut, Hartford, and the Cardiac Unit, Massachusetts General Hospital, Harvard Medical School, Boston (J.V.P., M.H.C., J.T.F., A.E.W.).

Correspondence to Chunguang Chen, MD, Division of Cardiology, Hartford Hospital, 80 Seymour St, Hartford, CT 06102.


*    Abstract
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 *Abstract
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down arrowResults
down arrowDiscussion
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Background Dobutamine stress echocardiography has been proposed as a diagnostic tool to identify viable myocardium. How regional wall thickening responds to dobutamine in the ischemic or short-term hibernating myocardium has not been adequately defined. We hypothesized that regional wall thickening would improve initially and subsequently deteriorate with incremental doses of dobutamine in viable myocardial regions supplied by a stenotic coronary artery. This study was undertaken to determine whether this biphasic pattern of regional function characterizes the response of ischemic or hibernating myocardium to dobutamine and to explore the factors and mechanisms that determine this response.

Methods and Results Twenty-six pigs in four groups were studied: a control group (n=5) to assess the response of myocardium perfused by nonstenotic coronary artery to incremental doses of dobutamine, and three experimental groups with a left anterior descending coronary artery stenosis producing acute myocardial ischemia (n=7), short-term myocardial hibernation for 90 minutes (n=7), and short-term hibernation for 24 hours (n=7) to determine the functional and metabolic response to dobutamine under these conditions. Regional coronary flow was reduced to 40% to 60% of baseline, with significant reductions of regional wall thickening as measured by two-dimensional echocardiography and sonomicrometers. An incremental dobutamine infusion from 2.5 to 25 µg · kg-1 · min-1 increased wall thickening and coronary flow without lactate production in the control group. In the other three groups, during the incremental dobutamine infusion, regional wall thickening improved initially, from 11.4±7.5% to 19.8±11.4%, P<.01, at dobutamine doses of 2.5 to 10 (4.5±2.2) µg · min-1 · kg-1 but deteriorated subsequently to 5.0±5.8% at the maximal dose of dobutamine of 12.6±4.1 µg · min-1 · kg-1. The initial improvement of regional wall thickening was associated with a small increase in regional coronary flow (from 0.53±0.18 to 0.68±0.25 mL · min-1 · g-1 myocardium, P<.05) and with regional lactate production. High doses of dobutamine did not further increase regional coronary flow but markedly increased lactate production and induced regional myocardial acidosis (pH 7.26±0.07). The biphasic pattern of response to dobutamine was observed in each of the three experimental groups. Both peak improvement and peak deterioration occurred earlier and at lower dobutamine dose levels in the group with acute ischemia compared with the group with short-term hibernation for 24 hours (P<.05).

Conclusions A biphasic response of wall thickening to incremental dobutamine with initial improvement and subsequent deterioration is characteristic of ischemic or short-term hibernating myocardium. The initial low-dose dobutamine infusion improved wall thickening in the ischemic or hibernating myocardial region to a modest level. This initial modest improvement was transient and at the expense of metabolic deterioration of myocardial ischemia, so that at higher doses during prolonged dobutamine infusion, wall thickening deteriorated, lactate accumulated, and myocardial acidosis developed.


Key Words: dobutamine • echocardiography • myocardium • ischemia


*    Introduction
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 up arrowAbstract
 *Introduction
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down arrowResults
down arrowDiscussion
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Dobutamine stress echocardiography has recently been introduced in clinical practice to detect coronary artery stenoses noninvasively1 2 3 4 5 and to differentiate viable from infarcted myocardium.6 7 8 The use of the test to diagnose coronary artery stenoses is based on the hypothesis that incremental doses of dobutamine can induce new or worsening wall motion abnormalities in left ventricular (LV) regions supplied by critically stenotic coronary arteries. In contrast, the use of dobutamine echocardiography to differentiate viable from nonviable dysfunctional myocardium is based on the hypothesis that dobutamine can improve regional wall thickening of viable myocardium.

Regional myocardial contractile dysfunction can result from myocardial infarction and scar or from viable myocardium that is dysfunctional because of myocardial ischemia with reduction of resting coronary flow,9 10 myocardial stunning,11 12 13 14 15 16 or hibernation.17 18 19 20 21 22 23 Hibernating or stunned segments are often perfused by a stenotic coronary artery, so that if incremental doses of dobutamine increase myocardial oxygen demand beyond the limit of supply, worsening regional wall motion would be expected. We hypothesized that regional LV wall thickening may improve initially and subsequently deteriorate with increasing doses of dobutamine in viable myocardial regions supplied by a stenotic coronary artery. This pattern is commonly observed clinically during dobutamine stress echocardiography; however, the biochemical and physiological determinants have not been investigated.

Therefore, this study was undertaken to determine the characteristic response of regional wall thickening to an incremental dobutamine infusion in segments supplied by a stenotic coronary artery and to explore the factors and mechanisms that determine this response. The study was conducted in a pig model with a coronary artery stenosis subtending a region of either acute myocardial ischemia or short-term myocardial hibernation.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
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Animal Preparation
The study protocol was approved by the Committee on Animal Care at Hartford Hospital, and the animal care guidelines of the American Heart Association were followed. Twenty-six pigs weighing 25 to 40 kg were fasted for 12 hours and premedicated with ketamine (1 mg/kg IM), penicillin (2200 U/kg IV), and gentamicin (3 mg/kg IV). General anesthesia was induced with ketamine (1 mg IM) and fentanyl and maintained with enflurane (0.5% to 1.5%) with an oxygen/nitrous oxide mixture (30% to 50%/50% to 70%). The animals were intubated and connected to a respirator. The ventilation rate and volume were adjusted to maintain normal arterial blood gases. The enflurane concentration was titrated to suppress the pain reflex but without deeper anesthesia so as to minimize the dose-dependent cardiodepressive and ventilatory effects of enflurane and to retain dynamic coronary autoregulation.23 Rectal temperature was monitored and maintained at 97°F to 98°F, and hypothermia was prevented by use of an electrically heated surgical table and drapes.

A midline thoracotomy was performed, and the heart was suspended in a pericardial cradle. A 7F Eppendorf catheter was inserted in the right femoral artery to monitor pressure and for blood samples. A 6F pigtail catheter was inserted through the atrial appendage into the left ventricle to monitor LV pressure and dP/dt. Left atrial pressure was monitored with another 6F pigtail catheter. The jugular veins were used to administer fluids and medications during the study. Full anticoagulation was achieved and maintained with heparin 200 IU/kg IV followed by 30 IU/kg IV every hour. In 8 animals, the interventricular vein running parallel to the left anterior descending artery (LAD) was dissected, cannulated, and connected to a three-way stopcock to monitor oxygen content, lactate, and pH; the coronary venous return was drained into a central vein. In the other 18 animals, a 3F coronary perfusion catheter was advanced retrograde via the coronary sinus to the same position.

To prevent focal coronary spasm due to surgical manipulation, 3% lidocaine drops were intermittently applied locally at the proximal LAD site at which the artery was manipulated. The LAD was carefully dissected free over 1 to 2 cm to accept a probe (Transonic Inc) to measure coronary flow. The cuff of the flow probe was carefully aligned parallel to the vessel to ensure accurate measurement. A hydraulic cuff occluder was placed around the LAD immediately distal to the flowmeter. The LAD was occluded briefly to delineate the central ischemic area, where a pair of ultrasonic crystals was implanted across the LV free wall to measure wall thickening. The hyperemic reaction of the LAD was determined by dividing the peak coronary flow after a brief occlusion (10 seconds) by the resting coronary flow. An LAD stenosis was created by gradually filling the hydraulic occluder with saline to reduce the resting LAD coronary flow.

Experimental Protocol
Baseline measurements of wall thickening by echocardiography and sonomicrometry, heart rate, LV pressure, aortic pressure, regional coronary flow and coronary venous lactate, H+ concentration, and oxygen content were obtained under stable conditions. Stability was defined as two consecutive measurements at 5-minute intervals with a pH difference <0.02, a coronary flow difference <3 mL, and a mean blood pressure difference <5 mm Hg before initiation of dobutamine infusion. During dobutamine infusion, measurement was obtained at the end of each stage (3 minutes). The response to incremental doses of dobutamine was assessed in a control group with no coronary stenosis and in three experimental groups: acute myocardial ischemia, short-term myocardial hibernation for 90 minutes, and short-term hibernation for 24 hours.

Control group. In the control group (n=5), no coronary stenosis was created. After baseline measurements, dobutamine hydrochloride was infused at 2.5, 5, 10, 15, 20, and 25 µg · kg-1 · min-1, with a 3-minute interval for each dose. The dobutamine infusion was terminated in 3 animals at 20 µg · kg-1 · min-1 because systolic blood pressure decreased by >20 mm Hg; the other 2 animals completed all stages of the infusion. All baseline measurements were repeated at the end of each dose, while the infusion of dobutamine was continued.

Acute ischemia group. In 7 pigs, a critical stenosis was produced to reduce LAD flow to 40% to 60% of the baseline level. Dobutamine infusion started after 20 minutes of coronary artery stenosis, when the regional ischemic metabolism is most apparent.21 22 The same dobutamine infusion protocol was used as described above for the control group. In all 7 animals, dobutamine was terminated when wall motion significantly worsened by visual assessment, with the onset of akinesis. Blood pressure decreased by >20 mm Hg in 3 pigs, and 2 developed ventricular tachycardia, including 1 that was successfully defibrillated when the rhythm degenerated to ventricular fibrillation. The LAD stenosis was released after the dobutamine infusion, and the animals were killed 3 hours later.

Short-term myocardial hibernation for 90 minutes. In the 7 animals in this group, a critical LAD stenosis was also applied to reduce resting LAD flow to 40% to 60% of the baseline level, with a regional decrease in wall thickening, as in group 1. All baseline measurements were repeated after 90 minutes, by which time myocardial ischemic metabolism had recovered, with cessation of regional lactate production. The dobutamine infusion was started at 100 minutes and was stopped in all 7 pigs when regional akinesia or dyskinesia developed by visual assessment. Two animals had a decrease in systolic blood pressure >20 mm Hg, including one with ventricular tachycardia. After the infusion, the LAD stenosis was released, and the animals were killed 3 hours later.

Short-term myocardial hibernation for 24 hours. The experimental protocol applied to the 7 animals in this group was identical to that used in the preceding group, except that the LAD flow reduction was maintained for 24 hours. The constancy of coronary stenosis was evaluated by serial measurements of coronary flow at 30 minutes, 60 minutes, 90 minutes, and 24 hours with the pigs in the same anesthetized condition. Mean transmural coronary flow was 0.55±0.11, 0.54±0.11, and 0.54±0.10 mL · min-1 · g-1 myocardium at 30 minutes, 60 minutes, and 90 minutes, respectively. After application of a stable LAD stenosis for 90 minutes, the chest was closed in layers, with the pericardium left open. Aspirin and intravenous heparin were given postoperatively to prevent thrombotic coronary occlusion. After 24 hours of LAD stenosis, the animal was reanesthetized and studied under the same anesthetized condition. Coronary flow was 0.56±0.12 mL · min-1 · g-1 myocardium at 24 hours, which was not different from that at 90 minutes after the stenosis. There were no differences in mean aortic pressure, heart rate, or LV end-diastolic pressure between measurements (P=NS). All measurements were performed with the pigs in the same anesthetized condition. Other baseline measurements were also repeated at 24 hours, and the dobutamine infusion protocol was carried out. The end point was the development of akinesia or dyskinesia by visual assessment in 6 pigs and a decrease >20 mm Hg systolic blood pressure in 1. The LAD stenosis was then released, and the chest was closed in layers with the pericardium left open. The animals were kept alive for 7 days to document the functional recovery of the stunned myocardium. One animal died 16 hours after the release of coronary stenosis due to excessive hemorrhage. In all surviving animals, epicardial echocardiograms were repeated at 1 week.

Echocardiographic measurements. Two-dimensional epicardial echocardiography was performed to evaluate the severity and circumferential extent of the reduction of regional myocardial wall thickening at the short-axis view of mid–papillary muscle level of the LV. Images were obtained from the epicardial surface of the right ventricle (Fig 1Down). Wall thickness was measured at the mid–papillary muscle level as described previously,24 modified to ensure a reproducible location. Internal landmarks were used to measure anterior and inferior segments of the myocardium reproducibly. At the mid–papillary muscle level, the ventricle was divided into anterior and inferior halves by a line (Fig 1Down, line A) connecting the midseptum and the midpoint of the posterior wall between the two papillary muscles. Anterior wall thickness was measured at the point at which the midanterior wall was intersected by a line (Fig 1Down, line B) that perpendicularly bisects line A (Fig 1Down). The inferior (control with normal coronary supply) wall thickness was measured at the opposite wall intersected by this line. The papillary muscle was excluded. In five cases, the line intersected a part of the anterolateral papillary muscle, and the anteroseptal wall most adjacent to the papillary muscle was selected for the measurement. This system was used for defining the location of the measurement of end-diastolic and end-systolic wall thickness and allowed for correction of cardiac systolic rotation and sliding motion. End-diastolic wall thickness was measured when the LV cavity was maximal. End-systolic wall thickness was measured when the LV cavity was minimal. Regional LV wall thickening was calculated as end-systolic minus end-diastolic wall thickness divided by end-diastolic wall thickness, expressed as a percentage. All echocardiographic measurements were performed by two observers who were blinded to each other's results. The mean values of measurements are presented.



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  		Figure 1. Echocardiogram illustrating the definition of the location on the anterior wall at which wall thickness was measured. At the mid–papillary muscle level, the ventricle was divided into anterior and inferior halves by a line A connecting the midseptum and the midpoint of the posterior wall between the two papillary muscles. Anterior wall thickness was measured at the point at which the midanterior wall was intersected by a line B that perpendicularly bisects line A. The inferior (control with normal coronary supply) wall thickness was measured at the opposite wall intersected by this line. The papillary muscle was excluded from the measurement.

Interobserver and intraobserver variability of the measurement of regional wall thickening was studied in 108 hemodynamic stages in 21 animals of the experimental groups. The measurement of wall thickening of one observer (16.8±15.6%) was not significantly different from that of another observer (18.2±15.9%) (P=NS). Agreement between observers' measurements was assessed by mean±SD of the difference between measurements of each observer according to Bland and Altman.25 No systematic error was noted by this test. The mean difference was 1.4±2.9%. The 95% CI of the difference between two observers was 7.2%. The correlation coefficient for regional wall thickening measurements by the two observers was .97 (P<.0001), with an SEE of 5.2%. Similarly, no significant difference was noted between measurements of each observer (P=NS), and the correlation coefficient between measurements on different days by the same observer was .98 (P<.0001), with an SEE of 4.1%. According to Bland and Altman's25 test of agreement of measurements, the mean difference between measurements by the same observer was 1.2±2.3%. Improvement in wall thickening was thus defined as an increase in regional wall thickening of beyond the 95% confidence limits of intraobserver variation, which was at least 6.0%. Sonomicrometer measurements of regional wall thickening were obtained in 24 hemodynamic stages in 4 animals to validate echocardiographic regional wall thickening measurements. Wall thickening measured with echocardiography (y) and sonomicrometry (x) correlated as y=1.47x-0.64, r=.89, SEE=7.6, P<.001. End-systolic wall thickening measured with echocardiography (31±29%) was slightly greater than with sonomicrometry (21±18.5%, P<.05). This good correlation but slight difference in absolute wall thickening measurements between sonomicrometry and echocardiography has been documented previously.26 The reason for this discrepancy is not clear. Less wall thickening measured by sonomicrometry may be related to some degree of focal myocardial trauma during implantation of sonocrystals.

Regional myocardial blood flow. Regional coronary blood flow was measured with a cuff flow probe connected to a transonic flowmeter (Transonic Inc). At the conclusion of each experiment, the flowmeter was calibrated against a known rate of blood flow to ensure the accuracy of measurements, and methylene blue was injected into the LAD to stain the tissue supplied by the vessel. The stained tissue was dissected and weighed to determine the regional myocardial mass perfused by the stenotic coronary artery. Coronary blood flow is expressed as mL · min-1 · g-1 wet tissue.27

Regional myocardial metabolic measurements. Arterial and coronary venous blood samples were obtained anaerobically in cold dry syringes containing heparin fluoride to inhibit glycolysis. Samples were divided for blood gases and lactate content, stored on ice, and processed immediately after the experiment. Blood gases were measured in duplicate, and the values were averaged. Plasma for lactate content was deproteinated with perchloric acid, neutralized with potassium hydroxide and imidazole buffer, and analyzed by the enzymatic method. Regional myocardial oxygen consumption was calculated by subtracting the coronary venous oxygen content from the arterial oxygen content and then multiplying the regional transmural blood flow supplied by the LAD. Lactate consumption/production was calculated by subtracting the coronary venous lactate from arterial lactate and then multiplying the regional transmural myocardial blood flow. A positive value indicates lactate consumption, and a negative value indicates production.

Pathological and histochemical morphology. Methylene blue was injected distally into the stenotic LAD to delineate the area at risk. The LV was cross-sectioned at 0.5-cm intervals from apex to base; the LV sections were immersed in a 0.09 mol/L sodium phosphate buffer (pH 7.4) containing 1.0% triphenyl tetrazolium chloride (TTC) for 30 minutes at 37°C to identify myocardial necrosis. Myocardium with deep red staining by TTC was considered viable, and unstained myocardium by TTC was necrotic. The area at risk, including any infarcted area if present, was dissected and weighed, as noted above. The myocardial sample in the area at risk was fixed with formalin or glutaraldehyde for microscopic examination. Transmural myocardial slices of each myocardial region, including TTC-identified necrotic area, were stained with hematoxylin and eosin. Necrosis was defined by hemorrhage, enhanced acidophilia, nucleolysis, and polymorphonuclear leukocyte margination and infiltration.

Statistical Analysis
All parametric data were expressed as mean±SD. Linear regression analysis was used to correlate regional coronary flow or flow-related parameters and wall thickening. Fisher's exact test was applied to analyze the effect of patchy myocardial necrosis on the initial improvement of regional wall thickening. ANOVA was used to examine differences in the measured or calculated index among the subgroups with and without myocardial hibernation. Stepwise multivariate regression analysis was used to determine the relation of the maximal improvement of regional wall thickening at low-dose dobutamine or deterioration at the maximal dose of dobutamine infusion to regional coronary flow, rate-pressure product, regional myocardial oxygen consumption, lactate production, and regional coronary venous pH. A value of P<=.05 was considered statistically significant.


*    Results
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*Results
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Control Group
The responses of hemodynamic parameters, regional wall thickening, coronary flow, and regional pH to the incremental dobutamine infusion in the normal control group are shown in Table 1Down. Regional wall thickening increased with increasing doses of dobutamine (Figs 2Down and 3Down), as did regional coronary flow. At a low dose of 2.5 µg · min-1 · kg-1, regional coronary flow increased from 1.04±0.22 to 1.64±0.65 mL · min-1 · g-1 myocardium, a mean increase of 57.6%, whereas mean increase in myocardial oxygen consumption was only 13.8% (Table 1Down), with a decrease in oxygen extraction between arterial and coronary venous blood from 49.2±8.6% to 45.1±2.4% (P<.05). At a maximal dose of dobutamine (Table 1Down), coronary flow increased by 140% from baseline, whereas myocardial oxygen consumption increased only 87.8%, with a further decrease in arterial coronary venous oxygen extraction to 39.2±5.6% (P<.01). These results indicate that the dobutamine-induced increase in coronary flow is not only a result of increased oxygen demand but also of direct coronary vasodilation of the normal artery. Dobutamine did not induce lactate production. The decrease in regional pH was slight and not statistically significant, even at the maximal dose (Table 1Down, Fig 3Down).


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  		Table 1. Hemodynamics, Regional Myocardial Function, Perfusion, and Metabolism in Control Group (n=5)



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  		Figure 2. Echocardiograms illustrating an example of the response of regional wall thickening to incremental dobutamine infusion documented by two-dimensional echocardiography in a control normal pig. Left, End-diastolic frames; right, end-systolic frames. Note that the wall thickening increased with increasing doses of dobutamine infusion. Maximal wall thickening of all segments with an obliterated ventricular cavity at end systole was seen at the maximal dose of dobutamine (20 µg · kg-1 · min-1).



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  		Figure 3. Graphs showing dynamic changes of wall thickening, coronary flow, lactate consumption, and coronary venous H+ concentration in regions supplied by a normal coronary artery in a control pig. Bas indicates baseline; dob2.5 to dob20, dobutamine doses of 2.5 to 20 µg · kg-1 · min-1.

Experimental Groups: Effect of Dobutamine on Regional Function and Metabolism
Data are presented for four points during the experiment: baseline; LAD stenosis; LAD stenosis with an early (low) dose of dobutamine, when the improvement in wall thickening was maximal; and LAD stenosis with the maximal dose of dobutamine, when wall thickening was usually minimal or absent. No significant differences among the experimental groups were seen in the overall pattern of the responses of regional wall thickening and coronary flow to dobutamine infusion (Table 2Down). A biphasic response, initial improvement and subsequent deterioration of wall thickening to incremental dobutamine doses, was the most common pattern observed in the ischemic or hibernating region (Fig 4Down). The initial improvement of wall thickening was from 11.4±7.5% to 19.8±11.4% (on average, 8.4%) in short-term hibernating or acute ischemic myocardial regions. This improvement was less than that in the normal inferior regions (P<.05), where wall thickening increased from 40.7±6.2% to 55.0±7.8% (on average, 14.3%). In all three experimental groups, the initial infusion with low-dose dobutamine improved wall thickening of the ischemic regions in 16 of 21 animals (Fig 5Down). The improvement peaked at different dobutamine doses, ranging from 2.5 to 10 (4.5±2.2) µg · kg-1 · min-1 in different animals (Fig 5Down) after dobutamine infusion for 3 to 9 (5.1±2.0) minutes. Thereafter, regional wall thickening deteriorated with higher doses of dobutamine in the ischemic or hibernating regions, and at the maximal dose of 5 to 20 (12.6±4.1) µg · min-1 · kg-1, only minimal thickening or even thinning (Fig 5Down) was found, whereas wall thickening in normal regions increased further (P<.05) from that of low doses of dobutamine. The mean wall thickening was 5.5±5.8% in the ischemic or hibernating regions and 60.1±7.2% (P<.01) in the normal coronary artery–supplied regions at the maximal dose of dobutamine. The mean time from beginning of dobutamine infusion to the maximal dose of dobutamine was 10.7±2.5 minutes. This biphasic pattern of regional wall thickening in response to dobutamine was observed in 16 of the 21 animals with LAD stenosis (Fig 5Down). Of the other 5 animals, 2 did not have any initial improvement, and 3 had a minimal initial improvement of <6% in regional wall thickening with dobutamine (Fig 5Down). The factors that may account for the biphasic response are explored in the following paragraphs.


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  		Table 2. Responses of Hemodynamics, Regional Myocardial Function, Perfusion, and Metabolism to Incremental Doses of Dobutamine in Acute Ischemia and Short-term Myocardial Hibernation



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  		Figure 4. Echocardiograms illustrating the biphasic response of regional wall thickening to incremental dobutamine infusion documented by two-dimensional echocardiography in the ischemic region. Left, End-diastolic (ED) frames; right, end-systolic (ES) frames. Note that (A) at control baseline stage, the anteroseptal and anterolateral walls (from the 1 to the 4 o'clock positions, indicated by arrows), supplied by a severely stenotic anterior descending artery, are severely hypokinetic (ED wall thickness of 5.0 mm, ES wall thickness [indicated by arrows] of 5.3 mm, wall thickening of 6%). (B) After the infusion of 5 µg of dobutamine, there was a significant improvement of regional wall thickening in the hibernating region (ED wall thickness of 5.2 mm, ES wall thickness of 6.5 mm, wall thickening of 25%). But the improvement was much less than that of the control region (wall thickening of 53%). (C) At the high dose of dobutamine of 20 µg · min-1 · kg-1, the anterior wall (arrows) became akinetic (ED wall thickness of 5.2 mm, ES wall thickness of 5.2, thickening of 0%). In contrast, the wall thickening (69%) in the normal control regions (from the 5 to the 12 o'clock positions) continued to increase. S indicates interventricular septum; P, posterior left ventricular (LV) wall.



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  		Figure 5. Graphs demonstrating changes of regional wall thickening at each dose level of dobutamine in acute ischemia (A), short-term hibernation of 90 minutes (B), and short-term hibernation of 24 hours (C). The peak regional wall thickening was observed with different doses of dobutamine and durations of dobutamine infusion in different pigs. The regional wall thickening at the maximal dose of dobutamine was the minimal thickening in every case. CAS indicates coronary artery stenosis; D2.5 to D25, dobutamine doses of 2.5 to 25 µg · min-1 · kg-1.

Rate-pressure product. Changes in heart rate–systolic pressure product did not correlate significantly with improvement of regional wall thickening (P=NS) at initial doses of dobutamine. At high doses of dobutamine, changes in rate-pressure product correlated significantly with deterioration in regional wall thickening (r=.46, P<.05).

Coronary flow. Low-dose dobutamine slightly (P<.05) increased coronary flow to the ischemic or hibernating regions (Fig 6Down, Table 2Up); however, no further (P=NS) increase was observed at higher doses (Fig 6Down, Table 2Up). Increases in coronary flow in the ischemic or hibernating regions were not associated with a significant change of arterial coronary venous oxygen extraction in acute ischemia (from 59.2±6.3% to 56.3±4.7%, P=NS), short-term hibernation of 90 minutes (57.2±11.9% to 55.9±12.3%, P=NS), or short-term hibernation of 24 hours (43.9±7.8% to 43.4±8.7%, P=NS). The initial increase in coronary flow correlated with improving regional wall motion (r=.53, P<.01). The decrease in regional wall thickening at higher doses occurred despite no changes in regional coronary flow (Table 2Up, Fig 6Down). At the maximal dose of dobutamine, coronary flow did not correlate with regional wall thickening (r=.21, P=NS). There was also no significant increase of arterial coronary venous oxygen extraction in the ischemic group (61.2±10.2%) at the maximal dose. But the increase of the oxygen extraction was significant in the hibernation groups (63.0±12.3%, P<.05, for hibernation for 90 minutes and 58.1±6.5%, P<.01, for hibernation for 24 hours) at the maximal dose of dobutamine.



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  		Figure 6. Graphs showing dynamic changes of coronary flow, wall thickening, lactate consumption, and coronary venous H+ concentration in regions supplied by a stenotic coronary artery in an animal with 24-hour myocardial hibernation. CAS indicates coronary artery stenosis; DOB2.5 to DOB25, dobutamine doses of 2.5 to 25 µg · min-1 · kg-1.

Oxygen consumption. Regional oxygen consumption increased (P<.05) initially with incremental doses of dobutamine but then, on average, did not increase (P=NS) significantly at the maximal dose (Table 2Up). In 6 animals, oxygen consumption decreased at the maximal dose, in association with deteriorating wall thickening and a decrease in blood pressure.

Lactate production and coronary venous pH. Lactate production began at the low doses of dobutamine (P<.05) and increased significantly (P<.01) with dose increments (Table 2Up, Fig 6Up). Similarly, regional pH started to decrease at low doses and decreased significantly at higher doses (Table 2Up). A significant decrease of pH was always accompanied by a decrease in regional wall thickening (Fig 6Up).

Myocardial morphology. No myocardial necrosis was detected in 16 of 21 animals in the experimental groups. The other 5 animals had patchy myocardial necrosis by TTC staining and confirmed by microscopic examination, involving 1%, 3%, 5%, 6%, and 3% of the area at risk by TTC. Two of these animals were in the acute ischemia group, 1 was in the short-term hibernation for 90 minutes group, and 2 were in the short-term hibernation for 24 hours group. The patchy necrosis involved mostly endocardium in and around the anterolateral papillary muscle. No necrosis was transmural or involved more than one third of the myocardial wall thickness. No initial improvement of regional wall thickening with dobutamine was noted in 2 of the 5 animals with patchy necrosis and in 3 of 16 without necrosis (P=NS). Thus, the presence of small patchy endocardial necrosis had no significant effect on the response of regional wall thickening to dobutamine in this study.

By multiple regression analysis, coronary flow (P<.001) correlated best with initial improvement of regional wall thickening. The rate-pressure product (P<.01) and regional coronary venous H+ concentration (pH) (P<.05) were independently related to the degree of deterioration of regional wall thickening at the higher doses of dobutamine.

Differential Response of Acute Ischemic and Hibernating Myocardium to Dobutamine
Baseline heart rate, rate-pressure product, coronary flow, and regional wall thickening were not significantly different among the acute ischemic, 90-minute hibernation, and 24-hour hibernation groups (Table 2Up). The coronary flow reduction was also similar in the three groups (Table 2Up). No significant intergroup differences were found in the presence or absence of a biphasic pattern of response to dobutamine infusion in regions supplied by the LAD stenosis (Fig 5Up). However, peak improvement of regional wall thickening occurred at 3.9±1.5 minutes after the start of the dobutamine infusion at a dose of 3.2±1.2 µg · min-1 · kg-1 in the acute ischemia group versus 6.0±2.1 minutes at a dobutamine dose of 5.8±3.4 µg · min-1 · kg-1 in the group of myocardial hibernation for 24 hours (P<.05). Similarly, the maximal deterioration of wall thickening (least thickening or most thinning) occurred after 8.5±2.3 minutes of the infusion at a mean dobutamine dose of 9.1±3.7 µg · kg-1 · min-1 in the acute ischemia group, sooner (P<.02) and at a lower dose than in the subacute hibernation group (12.3±2.9 minutes, 15.4±4.1 µg · kg-1 · min-1). For both time to peak improvement and time to peak deterioration, the 90-minute hibernation group did not differ significantly from the other groups. Regional coronary venous pH in the acute ischemia group was lower (P<.01) and myocardial lactate production higher (P<.01) than in the hibernation groups, with no significant differences between the 90-minute and 24-hour hibernation groups. Oxygen consumption and arterial coronary venous oxygen extraction were significantly (P<.05) lower in the hibernating groups than in the acute ischemic group at low doses of dobutamine. There was no significant difference in oxygen extraction between ischemic and hibernating groups (P=NS) at high doses of dobutamine.

Pattern of Functional Recovery of Myocardial Hibernation for 24 Hours
Epicardial echocardiograms repeated at 7 days after release of the stenosis demonstrated a significant recovery but a tendency to less regional wall thickening (29.8±6.9%) in the ischemic region than at baseline (32.0±5.5%). However, the difference did not reach statistical significance (P=NS) in this group with only 6 animals. In 4 animals, transthoracic echocardiography was performed every day after release of the stenosis, and functional recovery could be followed daily for 7 days. The functional recovery was gradual, with minimal changes in the first 2 days. In these animals (n=4), wall thickening was 12.3±4.1% with the stenosis for 24 hours, 14.5±7.8% on day 1, 14.8±5.6% on day 2, 16.4±6.7% on day 3, 20.4±7.0% on day 4, 23±5.4% on day 5, 25.5±6.5% on day 6, and 30.2±6.8% on day 7 after release of the stenosis. The wall thickening (30.2±6.8%) on day 7 after release of the stenosis was slightly less but not significantly different (P=NS) from that (34.2±5.7%) of baseline. There was no significant change (P=NS) of wall thickening in the normally perfused inferior wall from immediately (38.1±6.1%) to 7 days (35.3±6.7%) after release of the stenosis.


*    Discussion
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*Discussion
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This study demonstrates that an incremental infusion of dobutamine produces a biphasic response, with early improvement followed by deterioration of wall thickening in a myocardial segment perfused by a severe coronary stenosis. This response was observed in this porcine model in myocardium characterized as acutely ischemic, short-term hibernating maintained for 90 minutes, or short-term hibernating maintained for 24 hours. The initial improvement in regional wall thickening with low-dose dobutamine was modest, transient, and heterogeneous, with the maximal improvement at different dobutamine doses in different animals. In most cases, the initial low dose of dobutamine increased regional coronary flow with only a slight increase in rate-pressure product, so that wall thickening improved initially. In every case, however, regional wall thickening deteriorated with increasing doses of the dobutamine infusion. This worsening was associated with an imbalance in oxygen supply and demand characterized by increases in rate-pressure product without further increase of coronary flow and by myocardial lactate production and acidosis.

Effects of Dobutamine on Regional Wall Thickening and the Mechanism
Dobutamine has traditionally been used as an inotropic agent to increase myocardial contractility in the failing heart. Dobutamine stimulates the ß-receptor and increases regional wall thickening, with increases in heart rate and systolic blood pressure, resulting in increased oxygen consumption and ATP consumption.28 29 30 31 As demonstrated in this study, in regions supplied by nonstenotic coronary arteries, coronary flow increases adequately either via a vasodilatory effect or via autoregulation due to the increased oxygen demand of the oxidative process to regenerate sufficient ATP. Therefore, wall thickening increases with incremental doses of dobutamine.

In contrast, in regions distal to a flow-limiting coronary stenosis, the initial low doses of dobutamine transiently improved regional systolic function of the ischemic or hibernating regions. This improvement was associated with a small increase in regional coronary flow in both ischemic and hibernating regions. The initial inotropic augmentation of regional contraction by dobutamine was associated with deterioration of regional myocardial metabolism, as evidenced by lactate production and regional myocardial acidosis. At high doses of dobutamine, the increase in rate-pressure product exceeded the limits of regional coronary flow. Consequently, anaerobic glycolysis was activated, lactate (and probably other metabolites) accumulated, acidosis developed, and wall thickening decreased. Acidosis or other metabolites may interfere with intracellular calcium release or may decrease sensitivity of myofilament response to intracellular calcium and cause deterioration of regional wall thickening.28

Previous Studies
Although responses of ischemic,9 23 stunned,32 33 or hibernating myocardium23 to a single dose of dobutamine or dopamine have been reported previously, biphasic and dynamic changes in response to incremental dobutamine doses have not been examined systematically in previous experimental studies with short-term myocardial hibernation. Indeed, the responses to dobutamine of regionally ischemic myocardium supplied by a stenotic coronary artery have been controversial, with both improvement and deterioration of function reported in different studies.29 30 31 32 33 34 35 36 37 38 39 40 This discrepancy may be due to differences in animal models and in dobutamine administration. In our study, the improvement of regional wall thickening with low-dose dobutamine was more transitory in the setting of acute ischemia than in groups with short-term myocardial hibernation. This difference may be related to ongoing ischemic metabolism with no reserve of arterial coronary venous oxygen extraction in the former situation compared with partial or complete recovery of ischemic metabolism with some reserve of the oxygen extraction in hibernating myocardium, which may delay the dobutamine-induced metabolic deterioration.

Acute Myocardial Ischemia
In dogs with a coronary stenosis severe enough to reduce resting coronary flow and produce acute ischemia, Vatner and Baig30 demonstrated improvement in LV segmental shortening with a dobutamine infusion of 4 to 10 µg · kg-1 · min-1 for 7 to 10 minutes in both moderately and severely ischemic regions. In contrast, in pigs with a coronary artery stenosis that reduced regional wall thickening by 25% to 75% with acute ischemia, Schulz et al23 did not find any changes in end-systolic regional wall thickening at the end of 5 minutes of intracoronary dobutamine infusion at 2.5 µg · kg-1 · min-1. The intracoronary infusion of dobutamine may yield a higher dobutamine concentration in the myocardium than intravenous infusion with the same dobutamine dose. Further, in their pigs, coronary flow was delivered by a roller pump with constant flow rate, and transmural coronary flow decreased after dobutamine infusion, contrary to the results of Vatner and Baig30 and other investigators,29 31 37 38 in which dobutamine increased transmural coronary flow. Vatner and Baig noted that the change in heart rate induced by dobutamine correlated with changes in segmental shortening in the ischemic zone.30 This is compatible with our finding that the improvement of regional wall thickening with low-dose dobutamine is associated with an increase in regional coronary flow and minimal increase in heart rate or rate-pressure product.

Timing of the measurement of regional function is important to capture the improvement of regional function with dobutamine infusion. In the acute ischemia group in this study, the maximal improvement of regional wall thickening occurred transiently, within 3 to 6 minutes after dobutamine infusion was started at doses of 2.5 to 5 µg · kg-1 · min-1.

Short-Term Myocardial Hibernation
As with acute ischemia, the response of hibernating myocardium to incremental dobutamine doses has not been well defined. To the best of our knowledge, no previous experimental studies have examined the effect of the drug on noninfarcted dysfunctional myocardium subjected to a coronary flow reduction for 24 hours.10 20 In one group of 5 pigs with short-term myocardial hibernation (90 minutes), Schulz et al35 reported that a 5-minute intracoronary dobutamine infusion at 2.5 µg · min-1 · kg-1 slightly improved regional wall thickening. However, in another group of 5 pigs with the same reduction of coronary flow and the same dobutamine dose but for an unspecified duration, they reported a marked reduction in regional wall thickening from 15.3±3.6% to 4.3±6.7% after dobutamine, although no significant change was observed in endocardial coronary flow (0.15±0.06 versus 0.12±0.10 mL · min-1 · g-1, P=NS).35 They did not systematically address the dynamic aspect of the response of regional wall thickening to dobutamine.

In our study, the initial improvement of regional wall thickening lasted longer, with less lactate production and less myocardial acidosis in the hibernation groups than in the group with acute ischemia. There are several potential explanations for this difference. Hibernating myocardium has partially recovered from the metabolic disturbances of acute ischemia so that some energy stores21 22 are available to delay the onset of ischemic dysfunction. This is further supported by the fact that more oxygen could be extracted from the coronary venous blood in the 24-hour hibernating region than that in the acute ischemic region with dobutamine infusion. As shown in this study, arterial coronary venous oxygen extraction was maximal for acute ischemic myocardium (59.2±6.3%), and dobutamine infusion did not significantly change the oxygen extraction, while arterial coronary venous oxygen extraction was almost normal (43.9±7.8%) in the 24-hour hibernating regions and increased significantly with high doses of dobutamine infusion (58.1±6.5%). Second, ß-receptor downregulation in the hibernating myocardium may blunt or delay the response to dobutamine. The other potential explanation for this difference could be that a moderate reduction in flow for 24 hours provides a stimulus for collateral formation. However, such collateral flow is likely to be minimal within 24 hours in pigs.

Limitations of the Study
The major limitation of this study is that differences in myocardial perfusion between endocardial and epicardial layers were not determined. Although the metabolic and functional responses to dobutamine have previously been shown to be homogeneous throughout the myocardial layers,23 dobutamine may induce redistribution of myocardial perfusion from the endocardial to the epicardial layer, and this may contribute to deterioration of regional wall thickening at high doses of dobutamine. In our study, initial improvement of regional wall thickening was associated with an increase in transmural myocardial flow measured by flowmeter and a decrease in LV end-diastolic pressure, suggesting an improvement in both endocardial and epicardial flow. Transmural coronary flow at high doses of dobutamine did not significantly decrease from that at low doses of dobutamine infusion, and LV end-diastolic pressure at high doses of dobutamine increased from that at initial low doses, indicating that the endocardial perfusion may have decreased at high doses of dobutamine compared with that of low doses of dobutamine.

Coronary venous samples were drawn from a catheter inserted into the local cardiac vein parallel to the stenotic LAD in most cases. The measurements of oxygen extraction of coronary venous blood from arterial blood were 59.2±6.3% for the acute ischemic group and 57.2±11.9% for the group of hibernation for 90 minutes, less than those usually associated with lactate release from the myocardium.21 The relatively low oxygen extraction may reflect either abnormal vasodilation secondary to the anesthesia or an admixture of coronary venous drainage from ischemic and nonischemic regions, perhaps from nonischemic epicardium and ischemic subendocardium. The oxygen extraction (43.9±7.8%) in the group of hibernation for 24 hours was even lower and was not associated with lactate production. The mechanism cannot be determined from this study but may be related to changes in metabolism and oxygen consumption in the hibernating myocardium for 24 hours. However, further study should be designed with serial measurements of oxygen consumption, myocardial flow including subendocardial flow, and lactate consumption or production to investigate the mechanism.

Dobutamine-induced changes in regional coronary flow may be different in patients from those in an experimental animal model with an artificial stenosis. However, a small increase in regional coronary flow by dobutamine was also noted in patients with severe three-vessel coronary artery disease.38 Lidocaine was applied locally to the site of stenosis to prevent spasm due to manipulation; any change that dobutamine might induce on the cross-sectional dimension of a human coronary lesion would not occur in our experiments. The transstenotic gradient was not measured in this study, so that changes in regional flow could be due to changes either in the gradient itself or in vascular resistance, or a combination of both.38 The interval for each dose of dobutamine was 3 minutes, which may not be long enough to allow a steady state to be reached. Thus, whether the changes in function would be sustained during dobutamine infusion at any level cannot be established from this study. However, this dose protocol was chosen because it is used clinically for dobutamine echocardiography.

During the creation of the coronary stenosis and the test of hyperemic response, a preconditioning effect may have been produced. However, the hyperemic response was obtained by occlusion of the coronary artery for only 10 seconds, which would limit any preconditioning effect. During animal preparation, every effort was made to avoid compression of the coronary artery. Therefore, any preconditioning effect in this study would be minimal.

Only LAD stenoses and anteroseptal, anterior, and anterolateral ischemic regions were used in this study; previous studies suggest that the response to dobutamine can be extrapolated to other arteries and regions.30 31 Whether our experimental results apply in the setting of complex multivessel coronary disease or prolonged myocardial hibernation for more than 24 hours requires further investigation.

Clinical Implications
Several groups of investigators have reported that dobutamine echocardiography can identify viable dysfunctional myocardium that will recover after revascularization.6 7 8 41 42 43 Cigarroa et al8 studied 25 patients who underwent revascularization procedures; preoperative low-dose dobutamine echocardiography predicted that 9 of the 11 patients would show improvement of LV regional function after revascularization. Other investigators have reported lower sensitivities, in the range of 50% to 60%, with low-dose dobutamine.40 41 42

These studies have inherent limitations.8 40 41 42 To date, only small series have been reported, and the adequacy of revascularization is not usually documented. Regional wall thickening has been assessed visually, without an objective quantitative method. The effect of dobutamine on regional wall thickening has not been correlated with the extent and severity of the coronary lesions or with the reduction of coronary flow. The criteria to define viable myocardium differ among studies, as do the doses used and the duration of the dose levels. Each of these factors may account for the failure of dobutamine echocardiography to identify viable myocardium in some patients.

The mechanism of myocardial dysfunction is often uncertain in clinical studies because the level of myocardial perfusion is not readily available, and determination of the underlying mechanism of regional dysfunction (stunned versus hibernating myocardium) is often difficult.44 45 46 In experimental studies, stunned myocardium appears to respond to dobutamine, with improvement of regional wall thickening to a level comparable to normal.12 16 32 33 In contrast, as shown in this study, dobutamine produces only transient improvement that does not approach normal levels of function in acutely ischemic or short-term hibernating regions. The maximal improvement or deterioration of regional function of the ischemic or hibernating region occurred at different dose levels and durations of dobutamine infusion, indicating that no single dose can be used to characterize the inotropic response of hibernating myocardium.

This heterogeneous response of ischemic or hibernating myocardial wall thickening to dobutamine infusion should be considered in the clinical application of dobutamine echocardiography for detection of viable myocardium. Starting with low doses of dobutamine infusion to avoid an excessive increase of heart rate or systolic blood pressure and continuous echocardiographic monitoring of regional wall thickening are crucial to detect an improvement of regional wall thickening that may be unimpressive and transient in hibernating myocardium.

Summary
The most common response of regional wall thickening to dobutamine in this study was initial improvement followed by deterioration. This response can thus be considered characteristic of acutely ischemic or hibernating myocardium in association with a severe, flow-limiting coronary stenosis. Our results provide a physiological and biochemical explanation for this pattern. Initial low doses of dobutamine improve wall thickening, with a small increase of regional coronary flow and a minimal increase of rate-pressure product. But this initial improvement is modest, transient, and sustained at the expense of metabolic deterioration of myocardial ischemia, so that at higher doses during prolonged dobutamine infusion, wall thickening deteriorates, lactate accumulates, and myocardial acidosis develops. These insights could lead to a better understanding of the clinical findings from use of dobutamine echocardiography and to the development of better approaches to identify viable myocardium.


*    Acknowledgments
 
This study was supported by a grant from the Beatrice Fox Auerbach Foundation.

Received December 7, 1994; revision received February 19, 1995; accepted February 28, 1995.


*    References
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*References
 

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