Effects of Dobutamine at Maximally Tolerated Dose on Myocardial Blood Flow in Humans With Ischemic Heart Disease
Background This study tests the hypothesis in humans with ischemic heart disease that myocardial blood flow response to dobutamine is linearly correlated with blood flow response to adenosine.
Methods and Results PET with [13N]ammonia was used to measure myocardial blood flow at rest and during adenosine and dobutamine at the maximally tolerated dose. Myocardial segments were defined physiologically on the basis of blood flow response to adenosine: normal, ≥2 mL · min−1 · g−1; abnormal, <2 mL · min−1 · g−1; and “steal,” decline versus baseline ≥0.15 mL · min−1 · g−1. The patient population consisted of 11 men and 2 women. Dobutamine increased heart rate (79±22 to 115±28 bpm) and rate-pressure product (9748±2862 to 15 157±3433 mm Hg/min) significantly (both P<.01). Myocardial blood flow at rest in abnormal segments (0.50±0.23 mL · min−1 · g−1) was reduced (P<.001) versus normal (0.90±0.45) and steal (0.92±0.60). Nevertheless, in abnormal segments, blood flow increased versus rest (P<.001) with dobutamine (0.83±0.43) and adenosine (0.90±0.49). In steal segments, myocardial blood flow declined versus baseline (P<.001) with dobutamine (0.68±0.46) and adenosine (0.50±0.45). In normal segments, myocardial blood flow increased (P<.001) with dobutamine (2.16±0.99) and adenosine (3.10±0.90). Over the range of flows, the correlation between adenosine and dobutamine was good (r=.78, P<.0001). Although flow with dobutamine in normal segments correlated with rate-pressure product (r=.81, P<.05), the slope of the line was 2.7±0.8 (P<.02), and normalized blood flow (3.3±2.5 ×rest) exceeded normalized rate-pressure product (1.9±0.8 ×rest; P<.05).
Conclusions In humans with ischemic heart disease, myocardial blood flow responses to dobutamine and adenosine are linearly correlated over a wide range. The hyperemic response to dobutamine is in excess of that predicted by rate-pressure product and reflects the unmeasured inotropic, oxygen-wasting, and β2-agonist effects of the drug. Dobutamine induces coronary steal with a frequency approaching that of adenosine.
Previous studies of the effects of dobutamine at maximally tolerated doses on myocardial blood flow in patients with ischemic heart disease have indexed results either to coronary artery anatomy or to regional wall motion during dobutamine stress.1 2 Although both studies provide important information, neither evaluated regional myocardial blood flow responses to dobutamine with respect to directly measured maximal vasodilator capacity with adenosine. Because both regional wall motion and coronary artery anatomy have definite limitations as surrogates for maximal dilator capacity of the coronary circulation,3 4 it is difficult to use results of these studies to directly assess the true myocardial blood flow effects of the drug.
Indeed, a direct, quantitative comparison of myocardial blood flow responses to adenosine and dobutamine has not been reported in humans with ischemic heart disease. Moreover, the ability to categorize myocardial segments physiologically in terms of directly measured maximal vasodilator capacity with adenosine provides the opportunity (1) to quantify the extent to which the inotropic, β2-adrenergic agonist5 6 and oxygen-wasting7 effects of dobutamine augment myocardial blood flow above and beyond simple elevation of rate-pressure product in myocardial segments with proven normal maximal vasodilator capacity and (2) to address the issue of coronary “steal” with dobutamine, which has been considered to only a limited extent in previous reports.2 8 Accordingly, we tested the hypothesis that regional myocardial blood flow with maximally tolerated dobutamine would approach that of adenosine in segments with preserved maximal vasodilator capacity, whereas segments with evidence of impaired flow response with adenosine would exhibit blunted response to dobutamine as well. Furthermore, we tested the hypothesis that coronary steal, which has been shown to occur with adenosine,9 also may occur with dobutamine because of the potent inotropic and β2-adrenergic agonist properties of the drug.5 6
After approval was obtained from both the Radiation Safety and the Human Studies committees of the Massachusetts General Hospital, 13 patients were recruited at our institution between November 1, 1995, and November 30, 1996. Written informed consent was obtained from all patients. Exclusion criteria included any factor that precluded adequate or safe completion of PET with adenosine and dobutamine stress. These included unstable angina, uncontrolled left ventricular failure or atrial fibrillation, severe hypertension, recent (within 1 month of PET study) myocardial infarction, severe chronic obstructive pulmonary disease, and inability to lie supine for sufficient time to allow data acquisition.
PET imaging was performed on a whole-body tomograph (GE Medical Systems Scanditronix PC4096) in patients after an overnight fast according to a previously described protocol.4 10 Briefly, images were acquired in 15 contiguous sections simultaneously with center-to-center separation of 6.5 mm. After positioning in the scanner, a 10-minute transmission scan was performed to correct the emission data for attenuation. Next, ≈25 mCi of [13N]ammonia was administered with the patient at rest, with dynamic tomographic imaging begun just before injection. Data were collected for the first 3 minutes at 6 seconds per frame and then at 2 minutes per frame for 6 minutes. After image acquisition, radioactivity was allowed to decay for ≈30 minutes, at which time the count rate seen by the scanner was ≈7500 cps.
Next, 2 minutes after initiation of an intravenous infusion of adenosine (140 μg · kg−1 · min−1 over 5 minutes), dynamic data acquisition was begun, and several seconds later, ≈25 mCi of [13N]ammonia was administered intravenously over 30 seconds. Images were acquired in the same fashion as described above.
After another 30-minute period to allow for decay of radioactivity, dobutamine was infused intravenously beginning at 10 mg · kg−1 · min−1 and increasing every 3 minutes to a maximum of 40 mg · kg−1 · min−1. The maximally tolerated dose (34±7 mg · kg−1 · min−1; mean±SD) was maintained for as long as possible (average, 7 minutes; range, 3 to 12 minutes) to permit steady-state conditions during data acquisition. [13N]Ammonia was injected intravenously over 30 seconds at minutes 1 to 6 of the high-dose infusion (mean, 2.3 minutes). Clinical indications for termination of the infusion either before or during the 40-mg · kg−1 · min−1 dose were hypertension or hypotension, progressive angina, high-grade ventricular ectopic activity, attainment of 85% of predicted maximal heart rate, or intolerable discomfort related to forceful or frequent cardiac contraction. β-Blocker drugs were held for 48 hours before the study in all patients. The patient’s ECG and arterial pressure (Dynamap, model 845, Critikon Co) were monitored continuously during the study.
Attenuation-corrected [13N]ammonia images were reconstructed with a conventional filtered back-projection algorithm as 128×128-pixel images in the transverse plane normal to the long axis of the body. Filtering of the projection data was performed with a Hanning filter to yield output resolution of 7.8 mm (full width at half maximum). The [13N]ammonia scans (n=3) for each patient, corresponding to the last 6 minutes of data acquisition, were summed to permit placement of a region of interest over the left ventricular cavity. The region of interest was used to generate the arterial input function for the tracer kinetic model by which regional myocardial blood flow was determined.10 The arterial input function was not corrected for recirculation of labeled ammonia metabolites.11 A computer program developed at our institution was used in conjunction with the dynamic data to generate parametric (K1) images for rest and stress conditions.12 The images obtained provided a pixel-by-pixel representation of K1 and were used for analysis of regional myocardial blood flow.
PET Image Analysis
Three short-axis rings corresponding to the proximal, middle, and distal thirds of the left ventricle were constructed for each K1 scan as described previously.4 Briefly, circular regions of interest (≈8.5-mm radius) were placed over each ring at standard areas of interest: inferoseptum, midseptum, anteroseptum, anterior, anterolateral, lateral, posterolateral, and inferior zones. Regional myocardial blood flow was computed from values of K1.10 12
Myocardial segments were defined as normal, abnormal, and coronary steal based on blood flow response to adenosine. Abnormal segments had adenosine-stimulated blood flow <2 mL · min−1 · g−1, whereas normal segments had adenosine-stimulated blood flow ≥2 mL · min−1 · g−1. Coronary steal segments had a decline in myocardial blood flow with adenosine ≥0.15 mL · min−1 · g−1 versus baseline.
All data are expressed as mean±SD. Group mean values of continuous variables were compared by ANOVA with an appropriate post hoc multiple comparison test using commercially available software (Fisher’s protected least significant difference test, StatView V4.0, Abacus Concepts). Paired t tests also were used for comparison of myocardial blood flow at each intervention within segment type if repeated-measures ANOVA demonstrated a significant treatment effect. Wilcoxon signed-rank test for paired data was used to compare normalized rate-pressure product with normalized myocardial blood flow because the data were not normally distributed.
Thirteen patients (11 male and 2 female) 63±11 years old (range, 39 to 76 years) were studied (Table 1⇓). Previous myocardial infarction was present in 11 patients and was anterior in 5, inferior in 3, lateral in 1, and both anterior and inferior in 2. Four patients had previous coronary bypass surgery or coronary angioplasty. Study patients included 2 diabetics (1 insulin-dependent). Triple-vessel coronary artery disease was present in 8 patients, double-vessel disease in 1, and single-vessel disease in 3 (coronary angiography was not available in 1 patient).
Hemodynamic and Clinical Response to Dobutamine
Under baseline conditions, heart rate was 79±22 bpm, systolic arterial pressure 124±14 mm Hg, and rate-pressure product 9748±2862 mm Hg/min (Table 2⇓). In response to adenosine, there was no significant change versus baseline in heart rate, systolic arterial pressure, or rate-pressure product.
The maximal dose of dobutamine was 34±7 mg · kg−1 · min−1 and was given for 7±3 minutes. No patient had angina during dobutamine infusion, and only 1 had ECG evidence of myocardial ischemia, which resolved after the drug was discontinued. Ventricular ectopic activity was observed in 5 patients during dobutamine and also resolved when the drug was discontinued. Heart rate and rate-pressure product increased (P<.001) versus baseline in response to dobutamine, although systolic arterial pressure was unchanged. The peak heart rate attained with dobutamine was 74±19% of age-predicted maximum. No patient was given atropine.
Regional Myocardial Blood Flow
A total of 303 myocardial segments were available for analysis (Table 3⇓; Figs 1 through 4⇓⇓⇓⇓). Nine segments from 1 patient could not be analyzed because of positioning problems such that the segments were off the field of view.
Comparison of Dobutamine and Adenosine Blood Flow Responses
Under basal conditions, myocardial blood flow in abnormal segments (n=177; 13 patients) was reduced (P<.001) versus that of normal segments (n=84; 8 patients) and coronary steal (n=42; 6 patients). Similarly, blood flow responses to both dobutamine and adenosine were substantially reduced (P<.001) in abnormal versus normal segments. It should be noted, however, that in abnormal segments, myocardial blood flow with dobutamine and adenosine increased (P<.001) versus rest and that the absolute increments were virtually identical with each. Furthermore, when abnormal segments were considered by themselves, there was a good correlation (r=.75, P<.0001) over the entire range of blood flows (0.2 to 2.0 mL · min−1 · g−1) between the absolute response to adenosine and that to maximally tolerated dobutamine (Fig 1⇑).
In normal myocardial segments, blood flow increased substantially versus rest (P<.001) both with dobutamine and with adenosine. The increment with dobutamine, however, was less (72±30%) than that with adenosine (P<.001). Finally, when all segments were considered together, there was a strong correlation between absolute myocardial blood flow with dobutamine and adenosine (Fig 2⇑).
Dobutamine and Rate-Pressure Product
The correlation between the blood flow response to dobutamine and the rate-pressure product attained was examined for normal segments. All normal segments from an individual patient were averaged together because all were normal, and only one value of rate-pressure product was applied for each patient. Normalized (×rest) myocardial blood flow with dobutamine was plotted as a function of normalized (×rest) rate-pressure product (Fig 3⇑). A strong correlation was observed (r=.81, P<.02). More important, however, is the fact that the slope of the regression line was 2.7±0.8 (P<.02) and that normalized blood flow response to dobutamine (3.3±2.5 ×rest) was greater than that of normalized rate-pressure product (1.9±0.8 ×rest; P<.05, Wilcoxon paired signed-rank test).
Dobutamine and Coronary Steal
Myocardial segments that exhibited coronary steal with adenosine had rest blood flow nearly identical to that of normal segments and significantly greater (P<.001) than that of abnormal segments. By definition, myocardial blood flow declined versus rest in response to adenosine. The magnitude of the decline was substantial (≈45%). Myocardial blood flow also declined versus rest in response to dobutamine in these segments (P<.001). The magnitude of the decline, however, was less (P<.001) than that observed with adenosine (Fig 4⇑).
This study tested the hypothesis in humans with ischemic heart disease that myocardial blood flow response to maximally tolerated dobutamine is linearly correlated with blood flow response to adenosine. In fact, we demonstrated in myocardial segments with well-preserved maximal vasodilator capacity that myocardial blood flow with dobutamine also was substantial, although less (≈25% on average) than that of adenosine. In abnormal myocardial segments, defined as those in which MBF failed to increase above a level ≥2 mL · min−1 · g−1 with adenosine, a range of flow responses was observed, from essentially no increase versus rest to as much as 1.9 mL · min−1 · g−1 with adenosine. In these same segments, myocardial blood flow with dobutamine exhibited similar behavior (Fig 1⇑). Because most patients in this study had advanced ischemic heart disease, similar myocardial blood flow responses to vasoactive drugs with dissimilar mechanisms of action and potency are perhaps not surprising in segments exhibiting very limited flow reserve. However, as shown in Figs 1⇑ and 2⇑, dobutamine flow responses paralleled those of adenosine in segments with milder degrees of flow restriction as well as those with none at all. Moreover, as will be discussed in more detail below, in segments demonstrating steal with adenosine, there was a similar, albeit less potent, effect of dobutamine (Fig 4⇑). Accordingly, across the entire range of myocardial blood flow responses to adenosine from steal to hyperemia, dobutamine at maximally tolerated doses elicited a proportional, albeit less potent, response. The fact that blood flow responses to the drugs tended to parallel one another over the entire range suggests that conclusions derived in the present investigation, which included primarily patients with advanced ischemic heart disease, may apply to patients with less severe disease as well, although additional studies are required to establish this point.
We recognize, moreover, that adenosine causes dilation of the coronary circulation by a direct action on vascular smooth muscle and possibly endothelium as well. In contrast, dobutamine elicits coronary dilation primarily by indirect mechanisms related to its chronotropic and inotropic effects, although it too may cause primary dilation by means of its β2-agonist effects.5 Differences in mechanism of action between adenosine and dobutamine, especially in the setting of coronary steal, may translate into very different effects on left ventricular function, notwithstanding directionally similar effects on myocardial blood flow. Thus, even though proportional and in some instances very similar flow responses to the drugs were observed in the present study of patients with severe ischemic heart disease, important differences between the mechanisms of action of adenosine and dobutamine should not be overlooked in terms of the potential to cause myocardial ischemia (see below).
Coronary Artery Stenosis Anatomy and Regional Wall Motion as Surrogates for Myocardial Flow Reserve
Although the effects of maximally tolerated dobutamine infusion on myocardial blood flow have been investigated in humans with ischemic heart disease and compared with results of either coronary angiography or regional wall motion,1 2 8 potential limitations of both modalities for assessing the physiological status of the coronary circulation3 4 make it important to evaluate the coronary effects of dobutamine in terms of a physiological gold standard. We used adenosine for this purpose. The value of this approach is illustrated by the fact that previous studies that have investigated the relationship between coronary artery stenosis severity and myocardial blood flow response to dobutamine1 2 14 have shown substantial scatter and only weak correlations (r2=.24 to.39) between the two. Moreover, in another report, the correlation between myocardial flow fractional reserve, an invasive measure of stenosis severity, and regional wall motion response to dobutamine also was noted to be weak, with wide scatter in the data.14 Accordingly, efforts to predict regional wall motion or blood flow response to dobutamine based on detailed knowledge of coronary stenosis anatomy generally have not been reliable, especially in individual cases. Data from our own laboratory support this view.4 In contrast, failure of myocardial blood flow to increase with dobutamine was more predictive of development of a new or worsening wall motion abnormality with dobutamine2 and also is consistent with data previously reported from our laboratory.4
Myocardial Blood Flow With Dobutamine and Rate-Pressure Product
An important aspect of the blood flow response to dobutamine concerns its relationship to rate-pressure product in myocardial segments capable of an unrestricted flow response to adenosine. Although we observed a linear correlation between relative increment (versus baseline) in myocardial blood flow with dobutamine and relative increment in rate-pressure product similar to that reported by others,1 13 the slope of the regression line in the present study was 2.7 versus ≈1.0 reported by others.1 In the present investigation, moreover, in normal segments there was a significant difference between the increment in myocardial blood flow with dobutamine (≈3.3-fold, patient-based analysis, see Fig 3⇑) and the increment in rate-pressure product (≈1.9-fold). The difference in results between the present study and earlier ones1 2 13 may be related in part to longer total duration of dobutamine infusion at maximal dose in the present study as well as longer interval (≈5 minutes on average) between tracer injection and discontinuation of the drug. The excess in blood flow relative to rate-pressure product reflects the unmeasured contribution of contractility, oxygen wasting,7 and primary vasodilative effects5 6 of dobutamine. The present study is the first, to the best of our knowledge, to demonstrate these effects in myocardial segments with preserved maximal dilator capacity in patients with ischemic heart disease and provides insight into limitations of rate-pressure product as an index for assessing appropriateness of blood flow response to a drug or intervention, particularly catecholamines.
The extent to which myocardial blood flow increases in response to dobutamine in normally perfused myocardium of either normal volunteers or patients with ischemic heart disease also has been considered in relation to myocardial oxygen consumption measured by PET.7 13 In one study, dobutamine in normal volunteers increased rate-pressure product ≈2.4-fold, with comparable increases (≈2.5-fold) in myocardial blood flow and oxygen consumption. In the same study, however, myocardial blood flow and oxygen consumption in normal zones of patients with coronary artery disease increased in excess of rate-pressure product, although the difference (≈2.0-fold versus 1.6-fold, respectively) failed to reach statistical significance. A disproportionate increase in myocardial oxygen consumption (2.4-fold) relative to rate-pressure product (1.2-fold), however, has been reported by others7 in normal volunteers and is consistent with data obtained in the present investigation.
Dobutamine and Coronary Steal: Incidence and Clinical Implications
Previous studies1 2 8 13 provide only limited information concerning coronary steal with dobutamine. In two of the reports,1 13 steal was not observed. In the others,2 8 a decline in myocardial blood flow with dobutamine was observed in 3 patients, 2 of whom2 also had abnormal wall motion with dobutamine. Although comparison with an absolute measure of maximal dilator capacity was not made in either study, the decline in blood flow observed in previous reports2 8 to ≈60% to 80% of baseline was similar to that in the present study, in which 6 of 13 patients exhibited steal to ≈74% of baseline with maximally tolerated dobutamine. It is likely that differences in dose and duration of dobutamine infusion as well as patient population account for differences in frequency of occurrence. In animal models, dobutamine may15 or may not6 16 17 cause coronary steal, depending on species, stenosis severity, dose and duration of drug infusion, and other details of experimental design. Whether or not coronary steal occurs at therapeutic doses of the drug in humans with ischemic heart disease cannot be determined from the data obtained in the present study but should be considered especially if doses above the usually recommended therapeutic range (2.5 to 10 mg · kg−1 · min−1) are used.
Coronary steal has a number of important clinical implications. First, the data obtained in the present study demonstrate that defects in clinical, single-photon, myocardial perfusion images obtained after dobutamine stress may reflect not only a relative but rather an absolute reduction of myocardial blood flow. Because dobutamine, as shown in the present study, is generally a less potent coronary vasodilator than adenosine, the fact that it nevertheless is capable of inducing coronary steal is important to understand. This is particularly so because an absolute reduction in regional blood flow relative to baseline will obviously improve image contrast and hence defect recognition in clinical single-photon myocardial perfusion images.
In this regard, it should be recalled that clinically available myocardial perfusion tracers are diffusion limited and tend to plateau in the myocardium at blood flow levels >2 to 3 mL · min−1 · g−1.18 19 Thus, because tracer activity does not increase in proportion to blood flow above these levels, a region with flow of 2 to 3 mL · min−1 · g−1 may have no more tracer than one having flow of 4 to 5 mL · min−1 · g−1, and so they may be indistinguishable. A decline in blood flow in an abnormal area, however, would enhance image contrast and so facilitate defect recognition. Accordingly, the fact that dobutamine may induce coronary steal and the fact that clinical single-photon myocardial perfusion imaging is insensitive to blood flow >2 to 3 mL · min−1 · g−1 most likely account for results of a previous study that demonstrated similar sensitivity of adenosine and dobutamine as stressors for detection of coronary artery disease by SPECT imaging with 99mTc MIBI.20
Echocardiographic recognition of regional wall motion abnormalities during dobutamine stress, however, may be enhanced by coronary steal. This is true because myocardial oxygen demand is enhanced by dobutamine at the same time that it is responsible for an absolute decline in blood flow. The result will be more severe ischemia9 and hence more marked contraction abnormality,21 which in turn should be more easily detected in the clinical echocardiogram. Furthermore, even when adenosine induces steal, the degree of ischemia produced may not be sufficient to cause a detectable wall motion abnormality in transthoracic echocardiograms, as indicated by the fact that adenosine is less sensitive than dobutamine for detection of patients with ischemic heart disease when the diagnostic end point is development of a new regional wall motion abnormality.20
Critique of Methods
The limitations of coronary angiography for assessing physiological significance of coronary stenosis are becoming increasingly well known.3 Thus, we deliberately chose to index myocardial blood flow responses with dobutamine to an appropriate gold standard, namely, blood flow responses to adenosine. Accordingly, because the present study focused on the physiological status of the coronary circulation, detailed coronary angiographic data were not considered.
The definitions of normal, abnormal, and steal segments were based on the following considerations. A previous study of normal volunteers demonstrated with only one exception that myocardial blood flow response to adenosine was ≥2 mL · min−1 · g−1 in all vascular territories.12 Thus, to ensure that only segments having well-preserved maximal vasodilator capacity were included, we used that level to define segments with normal maximal dilator capacity. Abnormal segments, therefore, had values <2 mL · min−1 · g−1. Coronary steal was defined as an absolute reduction versus baseline myocardial blood flow of ≥0.15 mL · min−1 · g−1 with adenosine. In a previous study, we observed that 1 SD for a given blood flow measurement was 0.1 mL · min−1 · g−1 in our laboratory,10 and so a minimum decline of 0.15 mL · min−1 · g−1 was selected as a cutpoint. The fact that segments defined this way on average exhibited a decline of nearly 50% from baseline flow of ≈0.9 mL · min−1 · g−1 indicates that the criteria were effective in selecting myocardial segments that truly had a reduction in blood flow with adenosine. Moreover, the fact that these same segments exhibited a statistically significant decline in blood flow of ≈25% versus baseline with a second independent measurement made during dobutamine infusion (Fig 4⇑) strongly supports the physiological validity of the observation, argues persuasively against technical artifact or statistical noise as the cause, and represents new information not available in previous reports.1 2 8 13
The data obtained in the present study of patients with severe ischemic heart disease demonstrate that (1) myocardial blood flow response to maximally tolerated dobutamine is linearly correlated with absolute blood flow response to adenosine over the entire range of adenosine responses from steal to hyperemia but is ≈25% less potent at the extremes; (2) in myocardial segments with preserved vasodilator reserve, dobutamine induces a substantial hyperemic response that is out of proportion to elevation of rate-pressure product and reflects combination of inotropic, β2-agonist, and oxygen-wasting effects; (3) dobutamine at maximally tolerated doses is capable of inducing coronary steal and does so with a frequency approaching that of adenosine, albeit with lesser potency; and (4) although flow effects of the drugs may be directionally similar, mechanisms of action are very different, and as a result, rather different effects on left ventricular function may occur, particularly in the case of coronary steal.
Edie Sinagra assisted with preparation of the manuscript and coordination of patient scheduling. We wish to express our appreciation to the technical personnel of the PET and nuclear cardiology laboratories for dedicated and skilled assistance in the performance of these studies.
- Received April 14, 1997.
- Revision received June 27, 1997.
- Accepted July 15, 1997.
- Copyright © 1997 by American Heart Association
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