Author + information
- Received February 23, 1996
- Revision received July 3, 1996
- Accepted August 13, 1996
- Published online December 1, 1996.
- Lianglong Chen, MD,
- Lijie Ma, MD,
- Vazquez A. De Prada, MD,
- Minghui Chen, MD,
- Yue-Jin Feng, MD,
- David Waters, MD, FACC,
- Linda Gillam, MD, FACC and
- Chunguang Chen, MD, FACC⁎
- ↵⁎Address for correspondence: Dr. Chunguang Chen, Division of Cardiology, Hartford Hospital, 80 Seymour Street, Hartford, Connecticut 06102.
Objectives This study was designed to examine the effects of a beta-adrenergic blocking agent on the ischemic response to dobutamine stress and to determine the degree to which these effects can be abolished by the addition of atropine.
Background Whether beta-blockade affects the sensitivity of dobutamine stress echocardiography for the diagnosis of coronary artery disease has been controversial.
Methods In nine pigs, a left anterior descending coronary artery stenosis was created to reduce flow reserve (maximal/rest flow) to 1.1 to 1.9 without baseline regional wall motion abnormalities. This corresponded to a 50% to 90% diameter stenosis. Wall thickening was measured using epicardial echocardiography. Regional lactate production and coronary venous pH were monitored from an adjacent cardiac vein. A standard protocol of dobutamine stress echocardiography was first performed. After normalization of the ischemic abnormalities elicited with this infusion, esmolol was infused at 50 μg/kg body weight per min and the dobutamine test was repeated, with 1.0 mg of atropine added at the maximal dobutamine dose.
Results Without esmolol, dobutamine stress induced myocardial ischemia with a reduction in regional wall thickening and lactate production in all nine pigs. Multiple regression analysis revealed that coronary flow per heartbeat (p < 0.01) and lactate production (p < 0.05) independently correlated with regional wall thickening during dobutamine stress. The beta-blocker significantly reduced heart rate and regional oxygen consumption and altered the relation between coronary flow per heartbeat and regional wall thickening (p < 0.05) during dobutamine stress. Esmolol prevented dobutamine-induced ischemia (lactate production and wall motion abnormalities) in seven of nine pigs. The addition of atropine induced lactate production and a reduction in wall thickening in five of seven pigs in which ischemia had been prevented by beta-blockade. However, lactate production was higher and regional venous pH was lower with the baseline dobutamine infusion than with that performed after esmolol with atropine added at the maximal dobutamine dose (p < 0.05).
Conclusions A correlation between regional wall thickening and coronary flow per heartbeat was demonstrated during baseline dobutamine stress. Beta-blockade shifted this relation so that dobutamine stress-induced myocardial ischemia was attenuated. The mechanisms by which beta-blockade prevents dobutamine-induced ischemia appeared to be mainly through decreases in heart rate and rate of rise in left ventricular pressure, improvement of regional coronary flow per heartbeat and attenuation of regional ischemic lactate production. Adding atropine in conventional doses enhanced the ability of dobutamine stress to induce myocardial ischemia but did not completely abolish the effects of beta-blockade on either the severity of dobutamine-induced wall thickening abnormalities or regional metabolic disturbances.
Dobutamine stress echocardiography has been widely applied clinically for the noninvasive detection of coronary artery disease (1–10). Dobutamine stimulates beta1 and alpha1 receptors, resulting in positive inotropic and chronotropic effects. These pharmacologic actions are dose dependent, with predominant increases in contractility and cardiac output at lower doses and a progressive increase in heart rate at higher doses (11–14). The rationale for the use of dobutamine for stress testing is that it increases myocardial oxygen demand, thereby inducing ischemia in patients with coronary artery disease whose coronary flow reserve is impaired or limited.
Patients referred for dobutamine stress testing are often receiving beta-adrenergic blocking agents (3,15–17). With their negative chronotropic and inotropic effects, beta-blockers may prevent the ischemic response to dobutamine stress and may adversely affect the ability of dobutamine stress to detect myocardial ischemia. However, the extent to which beta-blockers prevent dobutamine-induced ischemic responses and potentially affect the sensitivity of dobutamine stress for the diagnosis of coronary artery disease in clinical studies has been controversial (3,15,18,19). Despite the current controversy, it is common clinical practice to stop beta-blockers temporarily 1 to 2 days or 4 half-lives of the agents before the dobutamine stress test (17) or to add intravenous atropine (15,18) at the maximal dose of dobutamine to increase heart rate. However, temporary discontinuation of beta-blockers may be hazardous, potentially exacerbating previous symptoms of angina, or precipitating unstable angina, acute myocardial infarction and even sudden death. Further, although adding atropine to the maximal dose of dobutamine has been shown to enhance the sensitivity of dobutamine stress for detecting coronary artery disease by increasing heart rate (15,18), the degree to which the protective effect of a beta-blocker can be abolished by adding atropine has not been well established.
Therefore, this study was designed to use a well-controlled pig model with left anterior descending coronary artery (LAD) stenosis to determine whether and through which mechanisms beta-blockers prevent dobutamine-induced ischemia, and to assess the degree to which the effects of beta-blockade can be reversed by adding atropine during dobutamine stress echocardiography. Because alterations in regional wall thickening are frequently used to define the results of dobutamine stress echocardiography, hemodynamic and biochemical factors related to the effect of dobutamine on wall thickening were first explored. Subsequently, the effects of beta-blockade on both wall thickening and related variables were examined.
- Abbreviations and Acronymns
- = left anterior descending coronary artery
- LV dP/dt
- = rate of rise in left ventricular pressure
Animal preparation. The study protocol was approved by the Committee on Animal Care at the Hartford Hospital, and the “Position of the American Heart Association on Research Animal Use” adopted by the Association in November 1984, were followed. Nine pigs weighing 25 to 45 kg were studied. A pig model of coronary artery stenosis was created as previously described (20). Briefly, general anesthesia was applied with isoflurane (0.5% to 1.5%) and with an oxygen/nitrous oxide mixture (30% to 50%/50% to 70%). The animals were intubated and ventilated with adjustments to maintain normal arterial blood gases. The isoflurane concentration was titrated to inhibit the pain reflex without oversedation with anesthesia to minimize the dose-dependent cardiodepressive effects and to retain dynamic coronary autoregulation. Rectal temperature was maintained at 97° to 98° F by use of an electrically heated surgical table and drapes. A femoral artery was cannulated to monitor blood pressure and for blood samples. Through left atrial cannulation, a 7F Millar catheter (Millar Instruments, Inc.) was placed with a distal transducer in the left ventricle and a proximal transducer in the left atrium for measuring left ventricular and left atrial pressures and the rate of rise in left ventricular pressure (LV dP/dt). A 3F coronary perfusion catheter was introduced retrogradely through the coronary sinus to the cardiac vein parallel to the stenotic LAD segment and connected to a three-way stopcock for monitoring oxygen content, lactate and pH. Full anticoagulation was achieved and maintained with heparin, 200 IU/kg body weight intravenously, followed by 30 IU/kg per hour. To prevent focal coronary artery spasm due to surgical manipulations, 3% lidocaine was intermittently applied focally at the proximal LAD site at which the artery was manipulated. The proximal LAD was dissected free to accept a coronary flowmeter probe (Transonic Inc), and a hydraulic cuff occluder was placed around the LAD immediately distal to the flowmeter. The hyperemic reactions of the LAD at baseline and with stenosis were determined by dividing the peak hyperemic coronary blood flow immediately after a brief occlusion of the vessel (10 s) by the rest flow. A graded LAD stenosis was created by gradually filling the hydraulic occluder to reduce the coronary flow reserve to 1.0 to 2.0.
Experimental protocol. Baseline measurements of heart rate, aortic pressure, left ventricular pressure, left atrial pressure, regional coronary flow, coronary venous lactate, pH and oxygen content were obtained under stable conditions, defined as two consecutive measurements at 5-min intervals with a difference of pH ≤0.02, coronary flow ≤3 ml and mean blood pressure ≤5 mm Hg. Stress echocardiography was performed with incremental doses of dobutamine at 3-min intervals (5,10,20,30 to 40 μg/kg per min). The dobutamine stress test was terminated when a significant regional wall motion abnormality was noted by on-line visual evaluation. During dobutamine only stress testing, each pig had 4 to 5 stage measurements including baseline 1, yielding a total of 42 stage measurements. The animal was then allowed to return to its baseline state with normalization of heart rate, blood pressure and wall motion. This process generally took 15 to 20 min. Subsequently, esmolol was administered with a loading dose of 50 μg/kg followed by an infusion of 50 μg/kg per min. The esmolol dose was subsequently adjusted to decrease heart rate by 10 to 20 beats/min while maintaining a systolic blood pressure of 90 mm Hg or higher. Atropine, 0.8 to 1.0 mg, was added at the maximal doses (30 μg/kg per min for five pigs and 40 μg/kg per min for four pigs) of dobutamine. All measurements were obtained at the end of each experimental stage. A total of 49 stages of measurements were obtained during dobutamine stress testing with infusion of esmolol.
Echocardiographic measurements. Two-dimensional epicardial echocardiography was performed using a mid-papillary short-axis level recorded from the epicardial surface of the right ventricle. Images were recorded on videotape for off-line wall thickening analysis. The end-diastolic frame of the echocardiographic images was selected using the Q wave onset of the electrocardiogram; the frame with the smallest left ventricular cavity was defined as end-systole. All premature heartbeats and the first postextrasystolic heartbeats were excluded. The endocardial and epicardial borders of each frame were manually traced according to the technique recommended by the American Society of Echocardiography and digitized using a commercially available computer system (Nova Microsonic). The papillary muscles were excluded. Subsequently, the left ventricle was divided into 100 equally spaced chords, and regional wall thickening was quantified for each chord with a centerline method as shown in Figure 1 (21). The chords were then grouped into eight segments, starting from the junction of the left ventricular inferior wall and the right ventricle as follows: inferior ventricular septum, mid-septum, anterior septum, anterior wall, anterolateral wall, posterolateral wall, posterior wall and inferior wall. The anterior septum and the anterior wall were considered as the regions supplied by LAD and the inferior wall was considered the control normal region. The wall thickening from 12 chords in each region was averaged for comparison.
Interobserver and intraobserver variability. All echocardiographic measurements were performed by two observers who had no knowledge of each others' results. One observer repeated measurements at least 3 weeks later. Interobserver and intraobserver variability for measurements of regional wall thickening was assessed using data from 36 hemodynamic stages in nine animals.
Regional myocardial blood flow measurements. Regional myocardial blood flow was measured with a cuff flow probe connected to a transonic flowmeter (Transonic Inc.). The flowmeter was calibrated against a known rate of blood flow to ensure the accuracy of the measurements. After completion of the experiment, the pigs were killed and their hearts were harvested. Methylene blue was injected into the LAD to stain the myocardium supplied by the stenotic vessel. The stained tissue was dissected and weighed to determine the regional myocardial mass perfused by the stenotic coronary artery. Regional coronary blood flow was expressed as milliliters per minute per gram of wet tissue.
Regional myocardial metabolic measurements. To inhibit glycolysis, arterial and coronary venous blood samples were obtained anaerobically in cold, dry syringes containing heparin fluoride. The samples were divided for blood gas and lactate analyses, stored on ice and processed immediately after the experiment. Blood gases were analyzed in duplicate, and the values were averaged. Plasma for lactate content was deproteinated with perchloric acid, neutralized with potassium hydroxide and imidazole buffer and then analyzed using 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 blood flow.
Statistical analysis. All data were expressed as mean value ± SD. Repeated measures one-way analysis of variance and the Tukey-Honestly test were used to compare parametric data. Least squares linear regression was used to test the correlation between parametric variables. The difference between correlations was examined by one-way analysis of co-variance. Multiple stepwise regression was applied to evaluate independent variables that were related to regional wall thickening during dobutamine stress. The variables included heart rate, mean blood pressure, rate-pressure product, regional coronary blood flow per minute, regional coronary blood flow per heartbeat and regional lactate production or extraction in 42 stages of measurements during dobutamine stress test. To account for the factor of multiple observations (4 to 5 stages) in each of nine pigs, we considered the multiple stages in each pig as an additional independent variable for the multiple regression analysis. Specifically, we averaged the values of wall thickening (y) from multiple observations for each pig, yielding a total of nine different mean values in nine pigs. The averaged value for each pig was then used for all stages in each pig and was treated as an additional independent variable (x) added to the other six independent variables (heart rate, regional coronary blood flow per minute, coronary blood flow per heartbeat, blood pressure, rate-pressure product, lactate extraction) for multiple stepwise regression analysis with wall thickenings in each stage as a dependent variable. A value of p < 0.05 was considered statistically significant.
Coronary blood flow reserve at baseline was 3.56 ± 0.42 and was reduced to 1.48 ± 0.26 (range 1.1 to 1.9) with LAD stenosis. Table 1 shows the alterations of hemodynamic variables, regional coronary blood flow, regional oxygen consumption, regional metabolism and regional myocardial function at each experimental stage, including control baseline, baseline after creation of LAD stenosis (stenosis baseline) and LAD stenosis with incremental doses of dobutamine without esmolol, with esmolol and with esmolol plus atropine.
Hemodynamic variables, regional coronary flow and oxygen consumption responses with and without beta-blocker during dobutamine stress (Table 1). Baseline. With intravenous esmolol, heart rate decreased significantly from 115 ± 15 beats/min at baseline to 94 ± 12 beats/minute (p < 0.05) after esmolol, as did dP/dt (from 1,336.3 ± 125.0 mm Hg/min at baseline to 1,035.7 ± 164.4 mm Hg/min with esmolol, p < 0.05). Regional coronary blood flow decreased (Table 1, p < 0.01). Coronary flow per heartbeat decreased (Table 1,p < 0.05), as did regional myocardial oxygen consumption (Table 1, p < 0.01). Systolic blood pressure remained unchanged (p > 0.05).
Dobutamine stress. With incremental doses of dobutamine without esmolol, there were significant increases in heart rate, dP/dt and regional coronary blood flow per minute (Table 1). A significant decrease in regional coronary flow per heartbeat was observed at doses of dobutamine ≥20 μg/kg per min. Systolic blood pressure increased slightly at lower doses of dobutamine (5 to 10 μg/kg per min), plateaued and subsequently slightly decreased at the maximal doses of dobutamine infusion.
Dobutamine stress with esmolol. With esmolol, incremental doses of dobutamine significantly increased heart rate, dP/dt, coronary blood flow and systolic blood pressure. However, at comparable stages, increases in heart rate and dP/dt with esmolol were not as great as without esmolol (Table 1). With esmolol, the maximal heart rate at maximal doses of dobutamine was 140 ± 10 beats/min and dP/dt was 2,415 ± 497 mm Hg/s, significantly less than those without esmolol (Table 1). At maximal doses of dobutamine, the regional coronary blood flow with esmolol was not different from the flow without esmolol. The coronary flow per heartbeat was, however, significantly higher in the stages with esmolol than the flow per heartbeat without esmolol (9.7 ± 2.2 vs. 6.9 ± 1.0 ml/beat per 1,000 myocardium, p < 0.01).
Effect of adding atropine. In the stages with esmolol, adding atropine at the maximal dose of dobutamine significantly increased heart rate (156 ± 8 beats/min), but not to the degree achieved by dobutamine alone in non-beta-blocked stages (191 ± 16 beats/min, p < 0.05). dP/dt and regional coronary blood flow were not significantly affected by adding atropine (Table 1, p = NS for each). Coronary flow per heartbeat was, however, reduced by adding atropine, but not to the degree achieved by dobutamine alone in non-beta-blocked stages (Table 1, p < 0.05). Atropine increased regional myocardial oxygen consumption from 5.28 ± 1.5 to 6.01 ± 2.57 ml/min per 100 g myocardium (p < 0.05). However, oxygen consumption after atropine was still significantly less than the level achieved by dobutamine alone in non-beta-blocked stages (6.01 ± 2.57 vs. 7.65 ± 3.31 ml/min per 100 g myocardium, p < 0.05).
Alteration of regional wall thickening during dobutamine stress.Interobserver and intraobserver variability. The difference in measurements of regional wall thickening between two observers (C.L. and M.L.) was 2.3 ± 5.4%. The difference in repeated measurements of wall thickening from the same observer was 1.9 ± 2.4% for C.L. The measurement error according to Bland and Altman (22) was 6.7% for the same observer.
Baseline wall thickening with and without esmolol. Normal ranges of wall thickening for each segment were established from baseline echocardiograms in nine pigs without coronary stenosis (Fig. 1). There was no significant change in regional wall thickening after the creation of the LAD stenosis, with values remaining within normal limits in all pigs (Fig. 2A). Intravenous esmolol decreased wall thickening from 38.9 ± 3.4% to 36.5 ± 3.3%, p < 0.05) in the regions with LAD stenosis as well as in the normal control regions (from 43.4 ± 1.5% to 36.5 ± 3.3%, p < 0.05).
Wall thickening alterations duringincremental doses of dobutamine infusion. Without esmolol, wall thickening in regions supplied by the stenotic LAD demonstrated a typical biphasic response, increasing at lower doses of dobutamine, peaking at about 10 μg/kg per min with a subsequent decrease at higher doses (Table 1). In control regions (the inferior wall), wall thickening increased significantly with low doses of dobutamine with no significant change after 20 μg/kg per min. In contrast, with esmolol, regional wall thickening in the segments supplied by the stenotic LAD continuously increased with incremental doses of dobutamine infusion in most pigs (Table 1, Fig. 2B).
Adding atropine to maximal doses of dobutamine. In the beta-blocked stages, the addition of atropine at maximal doses of dobutamine resulted in a decrease in wall thickening from 44.2 ± 5.9% to 34.4 ± 5.0% (p < 0.01) in the LAD regions, but not to the level achieved by dobutamine alone in non-beta-blocked stages (26.1 ± 3.0%, p < 0.05) (Table 1, Fig. 2A, B). In control regions, wall thickening was not significantly changed by atropine.
If regional myocardial ischemia or a positive dobutamine stress result was defined as unchanged (alteration of less than the measurement error of 6.7%) or decreased wall thickening during dobutamine stress, all nine pigs had positive test results in the non-beta-blocked state (Fig. 2A and 3). Esmolol prevented the reduction of wall thickening induced by dobutamine in seven of nine pigs (Fig. 2B and 4). With the subsequent addition of atropine, wall thickening decreased in seven of nine pigs (Fig. 2B and 4); of these, two of nine pigs showed a further reduction beyond that elicited by dobutamine alone, whereas five of nine pigs had reduced wall thickening only when atropine was added. The remaining two pigs showed no reduction in wall thickening at maximal doses of dobutamine with or without atropine (Fig. 2B).
Myocardial metabolic alterations with and without esmolol during dobutamine stress.Baseline. Regional myocardial lactate consumption after beta-blockade was not different from that in the non-beta-blocked state (p = NS). Similarly, regional coronary venous pH was similar before the creation of the stenosis and after LAD stenosis both with and without esmolol (p = NS). Regional myocardial oxygen consumption decreased significantly (p < 0.05) after esmolol (Table 1).
Dobutamine stress test. In non- beta-blocked stages, incremental doses of dobutamine increased regional lactate and reduced pH. At the maximal dose of dobutamine, regional lactate consumption (positive value) converted to lactate production (negative value in Table 1). In contrast, after betablockade, in seven of nine pigs regional lactate consumption was significantly reduced but did not convert to lactate production at maximal doses of dobutamine (Table 1).
Effect of adding atropine. Adding atropine at the peak dose of dobutamine increased lactate production (Table 1, p < 0.05), although regional pH fell (Table 1, p < 0.05). However, neither variable reached the levels achieved at the corresponding stage without esmolol (Table 1, p < 0.05 for each).
Factors related to regional wall thickening during dobutamine stress. Heart rate (r = 0.73, p < 0.01), rate-pressure product (r = 0.70, p < 0.01), regional coronary blood flow (ml/g per min) (r = 0.60, p < 0.05), coronary blood flow per heartbeat (r = 0.81, p < 0.01), myocardial lactate production (r = 0.64, p < 0.05) and myocardial oxygen consumption (r = 0.49, p < 0.05) all correlated significantly with wall thickening in the region supplied by the LAD during incremental dobutamine infusion without esmolol or atropine. However, multiple stepwise regression analysis revealed that only coronary flow per heartbeat (ml/g per 103,x1) and regional arterial-coronary lactate extraction (%, x2) were independent variables that predicted regional wall thickening during dobutamine stress (multiple R = 0.835, p < 0.001, y = 3.6x1 + 0.7x2 + 7.9). The stepwise regression procedure did not select the averaged wall thickening for each pig as a statistically significant independent variable (p = 0.17, partial r = 0.23). When we forced this variable into the final equation, multiple R2 was 0.6998 (r = 0.837, F = 22.46, p < 0.001) and was not different from the R2 of 0.698 (r = 0.835, F = 32, p < 0.001) without this variable in the final regression equation including only two statistically significant independent variables (coronary flow per heartbeat and lactate production). Therefore, the fact that there were multiple observations in each pig did not affect the results of the multiple regression analysis. Esmolol significantly altered the slope of the regression line between wall thickening and coronary flow per heartbeat (Fig. 5). The slope was flatter with esmolol than without esmolol, indicating that for an identical level of regional coronary blood flow and heart rate, regional wall thickening would be greater with esmolol if the coronary flow per heartbeat is at the lower range (usually at high doses of dobutamine), but wall thickening would be less with esmolol if the coronary flow per heartbeat is at the higher range (usually at low doses of dobutamine).
The degree of LAD stenosis and the degree of coronary blood flow reserve (1.48 ± 0.26) correlated significantly with a reduction in regional wall thickening at the maximal doses of dobutamine with or without esmolol (Fig. 6). However, esmolol shifted the slope of the regression line between a reduction in wall thickening and coronary blood flow reserve (p < 0.01). With esmolol infusion, in seven of nine pigs in which dobutamine stress did not induce a reduction in regional wall thickening, coronary blood flow reserve (1.53 ± 0.21) appeared higher than the flow reserve (1.17 ± 0.14) in the remaining two pigs with positive testing. By adding atropine, five of seven pigs with a negative dobutamine stress test in the presence of beta-blockade became positive. These five pigs appeared to have a lower coronary blood flow reserve (1.45 ± 0.22) than the other two animals with tests that remained negative (1.79 ± 0.11).
In this study, beta-blockade blunted the ischemic response to dobutamine stress, an effect only partially eliminated by atropine. Importantly, this study also provided hemodynamic and biochemical correlates of this phenomenon and demonstrated that beta-blockade causes a shift in the relation between regional wall thickening and coronary flow per heartbeat.
Dobutamine stress in the non-beta-blocked state. This study confirmed the results of previous clinical (3,9) and experimental studies (20), in that incremental doses of dobutamine induce a characteristic biphasic pattern in wall thickening in regions supplied by significant coronary artery stenosis but without baseline regional wall motion abnormalities. This consisted of an initial increase in wall thickening at low doses of dobutamine, with subsequent significant decreases in wall thickening to or below baseline values at higher doses. In contrast, in normally perfused regions, regional wall thickening increased significantly at low doses of dobutamine with either further increases or no change in wall thickening at high doses. This study further demonstrated that during dobutamine stress, the severity of the flow limitation (impaired flow reserve), heart rate and myocardial ischemic metabolic disturbances (lactate production and acidosis) interactively influenced alterations in wall thickening in areas supplied by a stenotic LAD.
Dobutamine stress in beta-blockade. In most animals, beta-blockade attenuated or completely prevented the ischemic response to dobutamine stress. This effect may be mediated through decreases in heart rate, rate-pressure product, dP/dt and regional myocardial oxygen consumption at peak dobutamine doses. Because total transmural regional coronary blood flow per minute was not significantly altered by intravenous esmolol during dobutamine stress, the slower heart rate with esmolol during dobutamine stress resulted in a relative increase in coronary flow per heartbeat. The increase in coronary blood flow per heartbeat and the decrease in regional myocardial oxygen consumption increased regional wall thick ening and prevented an ischemic response during dobutamine stress.
The degree to which beta-blockers prevented the ischemic response during dobutamine stress appeared to be related to the degree of reduction in coronary blood flow reserve and the severity of the coronary stenosis. In two of nine pigs with more severe coronary stenosis (coronary reserves of 1.07 and 1.27), esmolol did not prevent dobutamine-induced myocardial ischemia, whereas in seven of nine pigs with higher coronary flow reserves of 1.3 to 1.9 (1.53 ± 0.21), beta-blockade prevented dobutamine-induced ischemia.
Intravenous atropine added to the maximal dobutamine doses partially reversed the beta-blockade effect and induced ischemia in five of seven pigs in which ischemic response was prevented by esmolol. However, in two of seven pigs with less severely impaired coronary blood flow reserves of 1.7 and 1.9, adding atropine did not induce abnormal regional wall thickening or ischemic lactate production. Correspondingly, although atropine significantly increased heart rate, it did not completely abolish the effects of beta-blockade on heart rate, dP/dt, regional wall thickening and lactate production in this study.
Determinants of regional wall thickening during dobutamine stress. Because changes in regional wall thickening are frequently used to define the results of dobutamine stress echocardiography, this study evaluated a number of variables that potentially influence regional wall thickening. Multiple stepwise regression analysis indicated that coronary blood flow per heartbeat (regional coronary flow/heart rate) and myocardial lactate extraction were independently correlated with regional wall thickening, whereas systolic or mean blood pressure and the product of heart rate and systolic blood pressure were not. The absence of a relation between wall thickening and blood pressure may be explained by two potentially opposing effects. Thus, increases in blood pressure increase myocardial oxygen consumption and afterload, which may reduce regional wall thickening if coronary blood flow supply (reserve) is limited. However, increases in blood pressure also increase coronary perfusion pressure (mean aortic pressure - left ventricular diastolic pressure), and thus increase coronary blood flow (23,24). This increase in coronary blood flow may prevent ischemia and improve regional wall thickening by improving oxygen supply if the increase in oxygen demand does not exceed the increase in regional coronary blood flow.
The correlation between regional coronary blood flow per heartbeat and regional wall thickening was slightly altered by beta-blockade and by adding atropine (significant difference in slopes, p < 0.01 by analysis of covariance). Beta-blockade decreased heart rate during dobutamine stress. The decrease in heart rate resulted in an increase in coronary blood flow per heartbeat because total regional coronary flow was unchanged. As shown in Figure 5, it would be predicted that an increase in coronary blood flow per heartbeat would increase regional wall thickening and preventing dobutamine-induced reduction in wall thickening. It would be expected that adding atropine, by reducing coronary blood flow per heartbeat, would decrease regional wall thickening and produce an ischemic dobutamine stress response.
Coronary blood flow reserve correlated significantly with the percent change in wall thickening at the maximal doses of dobutamine, indicating a quantitative relation between regional wall thickening and the severity of the coronary artery stenosis. The relation was shifted upward by esmolol (Fig. 6). Thus, with identical coronary blood flow reserves, there will be greater wall thickening at peak dobutamine with esmolol than without it, potentially resulting in a negative test result. Atropine only partially reversed the effect of beta-blockade on the relation between coronary blood flow reserve and regional wall thickening at the maximal doses of dobutamine.
Previous studies. Although the ability of beta-blockade to prevent myocardial ischemia either at rest or during exercise has been well established (25,26), there has been controversy as to whether beta-blockade prevents the induction of regional left ventricular wall motion abnormalities during dobutamine stress (3,15,18,19). In their clinical studies, Sawada et al. (3) and Marcovitz and Armstrong (19) reported that beta-blockade did not significantly influence the sensitivity of dobutamine stress echocardiography for detecting significant coronary stenosis. In contrast, in a recent prospective study of 25 patients on and off beta-blockers, Fioretti et al. (18) showed that beta-blockade blunted the chronotropic effect of dobutamine and significantly reduced the ability of dobutamine stress to induce echocardiographic markers of myocardial ischemia. They showed that by adding atropine to the peak dose of dobutamine, heart rate was further increased and echocardiographically defined dobutamine-induced myocardial ischemia was enhanced (18). However, confirmation of the presence or absence of coronary artery stenosis by coronary angiography was performed in only 15 patients in the study by Fioretti et al. Thus, in addition to the relatively small number of patients studied, selection bias relative to the severity and extent of coronary stenosis may have contributed to discrepant findings in these clinical studies. In this animal study, all such confounding variables are well defined and tightly controlled.
Study limitations. There is no ideal system to quantify regional wall thickening (27). However, the modified centerline method used in this study is well accepted. Further, measurements were performed by two experienced echocardiographers and the values were averaged, minimizing potential observer bias. In our animal model, the quality of epicardial echocardiographic images was excellent, and thus clear delineation of epicardial and endocardial borders was possible. This method may not be applicable for clinical transthoracic echocardiographic images. However, images from transesophageal echocardiography could be comparable to the epicardial images, and quantification of wall thickening could be applied (28).
Four pigs in the initial phase of this study did not receive a maximal dose of 40 μg/kg per min when atropine was added. The dose of 30 μg/kg per min was defined as the maximal dose of dobutamine in the initial phase of this study and was based on the fact that all regional wall motion abnormalities were induced by a dobutamine dose ≤30 μg/kg per min without beta-blockade effects in this study. In the second phase of this study, a maximal dobutamine dose of 40 μg/kg per min was used if there was no regional wall motion abnormalities with esmolol. Even in this subgroup, only two of four pigs had a positive dobutamine stress test.
Results from this model with single-vessel disease may not be applicable in the setting of multivessel disease. Further, although the effects of anesthesia were minimized in this study, the hemodynamic responses observed could be different in the awake state. However, trends of changes in heart rate and blood pressure in this study were similar to those reported in awake humans during dobutamine stress either with or without esmolol and atropine (15,18).
Despite the above limitations, this study has its unique advantages. In this model, simultaneous measurements of regional LAD flow, myocardial oxygen consumption and metabolic variables (lactate and pH) as well as wall thickening were feasible, and the high quality of the epicardial echocardiographic images enabled quantitative analysis of changes in regional wall thickening during dobutamine stress. Myocardial ischemia defined by a reduction in regional wall thickening could therefore be correlated with hemodynamic and regional metabolic variables.
Clinical implications. This study has important clinical implications. A quantitative relation was demonstrated between coronary blood flow reserve or coronary blood flow per heartbeat and regional wall thickening and myocardial ischemic lactate production, indicating that dobutamine echocardiography provides not only qualitative but, to some extent, quantitative information on stress-induced myocardial ischemia.
Whether heart rate or the rate-pressure product should be used to quantitate or determine the adequacy of dobutamine stress has not been systematically studied. This study showed that heart rate or regional coronary blood flow per heartbeat correlated significantly with changes in regional wall thickening, although blood pressure did not. The rate-pressure product did not improve the correlation between regional wall thickening and coronary blood flow per heartbeat. Therefore, the results of this study suggest that during dobutamine stress, heart rate rather than the rate-pressure product should be used to monitor and quantitate the level of stress.
This study showed that beta-blockade prevented dobutamine-induced myocardial ischemia using either an echocardiographic (reduced wall thickening) or metabolic (regional myocardial anaerobic metabolism) criterion. Therefore, dobutamine stress echocardiography should be interpreted with caution in patients taking beta-blockers, especially in patients who have an inadequate increase in heart rate during incremental dobutamine infusion. Even when an adequate heart rate response is achieved by adding atropine, beta-blockade can prevent significant reductions in wall thickening or ischemic lactate production in the setting of stenoses with mildly impaired coronary blood flow reserve. However, in this study, by adding atropine, dobutamine stress echocardiography detected the majority (seven of nine pigs) of significant LAD stenosis of flow reserve 1.07 to 1.78), corresponding to 50% to 90% diameter stenosis in this study (23,24). Two pigs that continued to have negative results, despite adding atropine, had a less severe stenosis (flow reserves of 1.7 and 1.9, corresponding to 50% to 70% diameter stenosis). Therefore, this study supports the clinical practice of adding atropine to dobutamine stress in patients who are taking beta-blockers.
We thank Jeffrey Mathew, Hartford Hospital and John B. Newell, Massachusetts General Hospital for their statistical expertise. We also acknowledge the technical assistance of Edward Hall and William Dyckman.
This study was presented in part at the 44th Annual Scientific Session of the American College of Cardiology, New Orleans, Louisiana, March 1995. This study was supported by grants from the Hartford Hospital Research Fund and the Beatrice Fox Auerbach Foundation, Hartford, Connecticut.
- Received February 23, 1996.
- Revision received July 3, 1996.
- Accepted August 13, 1996.
- American College of Cardiology
- Fung AY,
- Gallagher RP,
- Buda AJ
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