(Circulation. 1996;94:3146-3154.)
© 1996 American Heart Association, Inc.
Articles |
Effects of Dobutamine Stimulation on Myocardial Blood Flow, Glucose Metabolism, and Wall Motion in Normal and Dysfunctional Myocardium
the Division of Nuclear Medicine and Biophysics, Department of Molecular and Medical Pharmacology and Division of Cardiology (operated for the US Department of Energy by the University of California under contract DE-FCO3-87ER60615), UCLA School of Medicine, University of California, Los Angeles, and Cedars Sinai Medical Center, Division of Cardiology (Y.-K.L., G.M.), Los Angeles, Calif.
Correspondence to Heinrich R. Schelbert, MD, Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA 90095-1735. E-mail hschelbert@pharm.medsch.ucla.edu.
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Abstract |
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Background This investigation examines the effects of inotropic stimulation on myocardial blood flow (MBF) and glucose metabolism (MRGlc) in dysfunctional myocardium through the use of positron emission tomography (PET).
Methods and Results Nineteen patients with chronic coronary artery disease and 12 normal volunteers were studied with 13N-ammonia, 18F-deoxyglucose, and PET and with two-dimensional echocardiography at baseline and during intravenous dobutamine (5 to 10 µg/kg per minute). At rest, MBF in mismatch regions (n=10) averaged 0.53±0.19 mL/g per minute and increased by 41.4±46.6% (P=.01) during dobutamine, whereas in match regions (n=16) MBF was 0.28±0.09 mL/g per minute at rest without an increase during dobutamine (26.4±47.3%; NS). Myocardium with normal rest MBF was classified as normal remote (normal wall motion, n=8) or abnormal remote (abnormal wall motion, n=11). Dobutamine raised MBF similarly in normal subjects and in normal remote regions (by 82±85% and 84±42%, P<.01) but by only 33±34% in abnormal remote regions. MRGlc declined by 49±28% (P<.005) with dobutamine in the normal subjects, remained unchanged in normal and abnormal remote regions of the patients, but increased in mismatch and match regions (by 49±74% and 46±77%; P<.05). Wall motion improved with dobutamine only in mismatch and abnormal remote regions but not in match regions.
Conclusions Blood flow–metabolism mismatch patterns are not consistently associated with a fixed downregulation of MBF; the increased contractile work in response to dobutamine stimulation is associated with an increase in MBF and a greater reliance on glucose utilization, possibly reflecting acute ischemia or alterations in substrate selection by chronically dysfunctional myocardium. Importantly, functionally impaired though normally perfused myocardium frequently exists in chronic coronary artery disease patients and may represent repetitively stunned or, more likely, remodeled left ventricular myocardium.
Key Words: tomography • blood flow • glucose • metabolism • coronary disease • myocardium
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Introduction |
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Positron emission tomography in patients with chronic CAD reveals several patterns of blood flow and glucose metabolism in hypoperfused dysfunctional myocardium. Segmentally increased 18F-deoxyglucose uptake has been referred to as blood flow–metabolism mismatch, a term used synonymously with reversible contractile dysfunction of "hibernating" myocardium.1 2 Conversely, a concordant reduction in glucose utilization and blood flow referred to as "match" signifies irreversible contractile dysfunction. The flow reserve tested with dipyridamole is markedly reduced or even absent in myocardium with flow-metabolism matches and mismatches.3 4 Yet, low-dose dobutamine can increase contractile function in dysfunctional segments with blood flow–metabolism mismatches.5 6 The reduction or loss of flow reserve together with the ability to increase contractile function raises the question of how such dysfunctional myocardium meets its energy requirements in response to the increased demand. Thus, the goal of this study was to quantify responses in flow and metabolism to low-dose dobutamine in flow-metabolism mismatch and match regions as well as in normally perfused but dysfunctional myocardium.
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Methods |
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Study Population
There were 19 patients with CAD and 12 normal volunteers. Patient age averaged 63±9 years; all had prior myocardial infarctions (Table 1
), 7 had prior coronary artery bypass graft surgery or coronary angioplasty, 5 had a history of heart failure, and 4 had non–insulin-dependent diabetes mellitus. Six of the 10 patients with mismatches were enrolled because of a positive dobutamine stress echocardiogram (ie, wall motion improved by 1 grade or more), which was more likely to be associated with a flow-metabolism mismatch than a match. The normal volunteers served to establish normal values of MBF and MRGlc at baseline and in response to low-dose dobutamine. Seven were male and 5 female. Their age averaged 37±18 years. None had cardiovascular risk factors or an abnormal ECG at rest. Those older than 50 years of age (n=3) had a normal ECG treadmill test. No patient took ß-blockers within 30 hours before the dobutamine study. Each participant signed an informed consent form approved by the Institutional Human Subject Protection Committee.
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Coronary Angiography
Eighteen of the 19 patients had undergone coronary angiography at 184±280 days before the PET study (Table 1
). Stenoses with 
70% diameter narrowing were considered significant. Twelve patients had no change in clinical symptoms between angiography and the PET study, 3 reported a worsening, and 3 an improvement of symptoms (ie, change >1 New York Heart Association functional class).
Study Protocol
With the use of a 2-day study protocol, MBF and MRGlc were measured at baseline on day 1. On day 2, wall motion was evaluated with two-dimensional echocardiography at baseline and during intravenous dobutamine followed by the measurements of MBF and MRGlc during low-dose dobutamine infusion. All volunteers and patients were studied first at baseline and then during dobutamine at an average of 7.6±7.2 days later.
Positron Emission Tomography
MBF was measured with 13N-ammonia (20 mCi) and MRGlc with 18F-deoxyglucose (10 mCi) as described previously.7 8 For the day 2 study, dobutamine infusion was started 10 minutes before the 13N-ammonia and 18F-fluorodeoxyglucose injection at the same dose used for the dobutamine echocardiogram (ie, 5 or 10 µg/kg per minute). The dobutamine infusion was continued for 2 minutes after the injection of 13N-ammonia. For the 18F-deoxyglucose study, dobutamine was infused throughout the entire image acquisition sequence in order to maintain steady-state conditions.
Heart rate, blood pressure, and 12-lead ECGs were recorded twice during the first 2 minutes of the 13N-ammonia and every 5 minutes during the 18F-deoxyglucose image acquisition sequences. The RPPs listed in Table 2 were obtained during the 13N-ammonia study. Venous blood for determination of glucose was withdrawn at the time of the 18F-deoxyglucose injection and again 10 and 60 minutes later. Plasma lactate, free fatty acid, and insulin levels in venous blood were determined at 10 minutes after 18F-deoxyglucose administration. The hemodynamic and plasma substrate measurements were averaged to obtain a mean value.
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PET Image Analysis
The serially acquired image data were reconstructed into sets of 15 transaxial images each and then reoriented into 6 short-axis cuts.9 Short-axis cross sections of the last serially acquired 13N-ammonia or 18F-deoxyglucose image sets were assembled into polar maps. The 13N-ammonia, 18F-deoxyglucose, and their difference polar maps were then compared with normal reference polar maps to (a) identify regions with reduced blood flow and (b) classify these regions into matches and mismatches.10 If regional 13N activity concentrations were within 2 SD of the normal mean in-plane activity, a segment was considered normal. Such "normally perfused regions" were categorized according to their wall motion by echocardiography at baseline into those with normal wall motion (defined as "normal remote regions") and those with impaired wall motion (wall motion score <3, see below; defined as "abnormal remote regions"). If 13N activity was >2 SD below the normal mean, myocardium was defined as hypoperfused. Its extent was estimated from the fraction of pixels within the LV myocardium that was below this threshold. The perfusion defect severity represented the average reduction in 13N activity in the hypoperfused region.11 A flow-metabolism mismatch was present if the 13N and 18F activity difference was >2 SD above the normal mean, whereas a match defect represented a concordant reduction in 13N and 18F activity, both 2 SD below the normal mean.
Two-dimensional Echocardiography
Because the study sought to test the response to low-dose dobutamine, the target infusion rate was 10 µg/kg per minute. In the 13 patients who underwent echocardiography at UCLA, apical four- and two-chamber long-axis and parasternal short-axis views were recorded at baseline. Dobutamine was then infused intravenously during ECG monitoring, initially at a rate of 5 µg/kg per minute for 10 minutes; if tolerated well, the dose was increased to 10 µg/kg per minute for another 10 minutes. At each stage, identical views were recorded. Blood pressure and heart rate were recorded every 3 minutes. All 13 patients underwent the dobutamine PET study on the same day. The 6 patients undergoing echocardiography in other hospitals were studied in the same fashion except that the infusion rate was increased to 10 µg/kg per minute after only 3 minutes at a starting dose of 5 µg/kg per minute. The time interval between echocardiography and the dobutamine PET study in these 6 patients averaged 12.1±10.3 days.
On each echocardiographic view, the myocardium was divided into six equal segments. Wall motion in each segment was graded by one of three observers, who was unaware of the PET findings, using a four-point scale (3, normal; 2, mild hypokinesis; 1, severe hypokinesis; and 0, akinesis/dyskinesis). The echocardiographic segments were assigned to six tomographic short-axis regions as described previously12 : anterior, anterolateral, inferolateral, inferior, inferoseptal, and anteroseptal, which were divided further into basilar, midventricular, and apical. A wall motion score was obtained for each PET region from the sum of the grades for each segment divided by the total number of segments analyzed. Again, segments with normal 13N-ammonia uptake and normal wall motion were defined as normal remote and segments with abnormal wall motion (grades 0 to 2) as abnormal remote regions. The LV ejection fraction was determined echocardiographically with the use of biplane Simpson's rule.13
Quantification of Myocardial Blood Flow and Glucose Utilization
In the normal volunteers, three 90° sectorial ROIs were assigned to the territories of the three major coronary arteries.14 The sectorial ROIs in the patients were defined by the operator as normal or hypoperfused, according to the polar map findings. In hypoperfused regions, the sectorial ROIs were assigned to the myocardium with the most severely reduced 13N activity. To ascertain identical ROI placement to the 13N-ammonia and 18F-deoxyglucose images, the same angle of origin was used for the sectorial ROI on the four image sets. A small ROI (25 mm2) was placed in the LV blood pool on the last frame. The ROIs were copied to all serially acquired image frames and time-activity curves derived. The 13N and 18F activities were corrected for partial volume effects, with a recovery coefficient assuming a uniform wall thickness of 1 cm for the LV myocardium.15 MBF was estimated from the arterial input function of 13N-ammonia and the myocardial tissue time-activity curve16 and MRGlc by Patlak analysis and parametric imaging.17
Statistical Analysis
Mean values are given with standard deviations. Group data were analyzed with Student's t test for paired or unpaired data. One-way ANOVA was used for comparison of intergroup differences and the nonparametric Mann-Whitney U test to compare wall motion scores between dysfunctional myocardial segments with a correction for multiple comparisons. Subgroups of patients were compared with the Wilcoxon signed rank test. MBF was correlated with wall motion scores with the use of linear regression analysis. Probability values <.05 were considered statistically significant.
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Results |
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Hemodynamic Findings
The hemodynamic findings at baseline and during dobutamine infusion are listed in Table 2
. Dobutamine infusion was generally tolerated well and was limited to 5 µg/kg per minute in only two patients because of palpitations. There were no ECG changes or symptoms indicative of ischemia. During the 13N-ammonia studies, dobutamine raised the RPP by 73±38% in the normal volunteers and by 39±44% in the patients. Baseline and dobutamine RPP were similar in normal volunteers and patients. The mean RPP during the 18F-deoxyglucose study in the volunteers was 7530±1662 mm Hg·min-1 at rest and 12 765±2222 mm Hg·min-1 during dobutamine infusion (P=NS versus 13N-ammonia study). The corresponding values in patients were 8046±1467 and 11 027±3036 mm Hg·min-1. Thus, in volunteers and patients, RPPs were similar during the 18F-deoxyglucose and the corresponding 13N-ammonia study. Heart rate and blood pressure during the 18F-deoxyglucose study remained constant throughout the 1-hour infusion of dobutamine in both volunteers and patients. The greater increase in RPP in the normal volunteers than in the patients was due to a greater rise in systolic blood pressure (38±9% versus 9±17%, P=.0002), whereas diastolic blood pressure remained unchanged and heart rates increased similarly in both groups (both 26±22%).
Polar Map Findings
The distribution of 13N-ammonia and 18F-deoxyglucose at baseline and during dobutamine was normal in the 12 normal volunteers. In the 19 patients, polar map analysis of the baseline studies revealed 10 mismatch and 16 match regions; 12 patients exhibited 1 hypoperfused region (Table 1) while 7 patients revealed 2 regions, one consistent with a match and the other with a mismatch. All perfusion defects, which were rather extensive, corresponded to a wall motion abnormality; their extent may not have fully matched the extent of the perfusion defect because no exact registration technique was used. Dobutamine stress did not change the extent of perfusion defects (41.3±13.6% at rest versus 44.8±15.0%, P=NS) or of mismatches (22.9±7.0% versus 23.4±5.2%) or the perfusion defect severity (23.2±11.7% versus 24.2±10.2%; NS), nor did it induce new flow defects as evidenced by polar mapping.
Echocardiographic Findings
The LV ejection fraction averaged at baseline 34±12% (Table 1) and increased with dobutamine to 40±14% (P<.0001). At baseline it was higher in patients with normal remote than in patients with abnormal remote myocardium (42±11% versus 28±8%, P<.01). The wall motion score in normal remote regions remained 3±0 with dobutamine because the scoring system did not include a grade for hyperkinesis. None of the normal remote regions developed a wall motion abnormality with dobutamine. The wall motion score in abnormal remote regions improved by a score of 1 in 5 of 11 regions; it averaged 1.8±0.5 at baseline and 2.4±0.5 (P<.005) during dobutamine. In mismatches, wall motion improved in 7 of 10 regions, with an average increase in wall motion score from 1.7±0.4 to 2.6±0.5 (P<.005) during dobutamine infusion. In contrast, only 2 of 16 match regions improved wall motion by at least one score, while the average wall motion score remained unchanged (0.8±0.7 versus 1.0±0.7, P=NS).
Coronary Anatomy
Coronary angiography in the 18 patients revealed two-vessel disease in 9 patients and three-vessel disease in the other 9. Five of 8 normal remote regions were supplied by vessels without and 2 by vessels with significant stenosis. Six of 11 abnormal remote regions were supplied by vessels without and two regions by vessels with significant stenoses (99% and 95%). In 3 regions, the vessels were completely occluded.
Quantitative Findings
Substrate and Insulin Levels
In the normal volunteers, dobutamine infusion raised plasma free fatty acid and insulin levels, whereas glucose and lactate levels remained unchanged (Table 2). In contrast, in the patients, only plasma insulin levels increased during dobutamine infusion. Plasma substrate and insulin levels were similar in diabetic and nondiabetic patients.
Myocardial Blood Flow
In the normal volunteers, MBF at rest averaged 0.68±0.16 mL/g per minute and increased to 1.21±0.24 mL/g per minute with dobutamine (P<.0001). Mean MBFs were correlated with the RPP (r=.87; P<.0001). In the patients, MBF at baseline in normal and abnormal remote regions averaged 0.73±0.23 mL/g per minute and 0.67±0.13 mL/g per minute, respectively, and 1.23±0.38 mg/g per minute (P=.01) and 0.88±0.23 mL/g per minute (P=.01) during dobutamine infusion (Table 3). A correlation between RPP and MBF was found for the normal remote but not for the abnormal remote regions. Blood flow averaged 0.53±0.19 mL/g per minute in mismatch and 0.28±0.09 mL/g per minute in match regions, respectively. With dobutamine, blood flow increased only in mismatch (0.73±0.29 mL/g per minute; P<.05) but not in match regions (0.36±0.17 mL/g per minute; P=NS). At baseline, MBF was similar in normal volunteers, normal remote regions, abnormal remote regions, and mismatches but was lower in match regions (P<.05). However, relative blood flows in mismatches (as a percentage of blood flow in the normal remote region in the same patients; n=5) averaged 72±11% at baseline (P<.005) and 74±12% during dobutamine (P<.05). In the patients with abnormal remote myocardium (n=5), relative blood flows averaged 75±13% (P<.05) at baseline and 66±15% (P<.01) with dobutamine. The corresponding values for matches were 39±17% (P<.01) at baseline and 32±19% (P<.005) during dobutamine infusion compared with normal remote regions (n=6) and 48±15% at baseline (P<.0001) and 40±14% (P<.0001) with dobutamine compared with abnormal remote regions (n=10). Compared with the 84±42% dobutamine-induced increase in MBF in the normal volunteers (Fig 1), the response to dobutamine was attenuated (P<.05) in the abnormal remote regions (33±34%), mismatches (41±47%), and matches (36±59%). In contrast, the flow increase in normal remote regions (82±85%) was similar to that in the normal volunteers. When the changes in blood flow in mismatch regions were compared with those in remote myocardium (both normal or abnormal) in only the 10 patients with mismatches (Fig 2), then the increases in mismatch regions no longer differed from those in the corresponding remote regions (41.4±46.6% versus 51.6±56.5%; NS). A similar comparison in the 16 patients with flow metabolism matches revealed a lesser flow increase in match than in remote regions (26±48% versus 59±69%; P<.05).
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There was no significant correlation between resting MBF and the wall motion score or between changes in blood flow and in wall motion scores in either type of dysfunctional myocardium (abnormal remote region, mismatch, or match). Thus, improvement in wall motion was not consistently associated with an increase in MBF and vice versa. In fact, wall motion improved in 6 of 19 segments without a flow increase. Conversely, MBF improved in 7 match regions by 20% without improvement of wall motion.
Rates of Glucose Utilization and Glucose Extraction
MRGlc decreased with dobutamine in the normal volunteers by 49±28% (Table 2), whereas no significant changes occurred in normal and abnormal remote regions of the patients (Fig 1). In contrast, MRGlc increased in mismatch and in match regions (Table 4). Comparison of the changes only in the patients with mismatches (Fig 2) shows that MRGlc increased more in mismatch than in the corresponding remote regions (46±72% versus 16±68%; P<.05). The same was true for the patients with matches in which MRGlc increased more in match regions than in remote myocardium (41±74% versus 12±77%; P<.05). Changes in MBF were unrelated to changes in MRGlc in normal volunteers and in patients. Glucose extractions at baseline (MRGlc divided by MBF) were similar in normal volunteers (0.75±0.25 µmol/mL), normal (0.72±0.46 µmol/mL; Fig 3) and abnormal remote myocardium (0.70±0.28 µmol/mL), and mismatches (0.98±0.40 µmol/mL). Yet, glucose extraction in matches (0.57±0.25 µmol/mL) was lower when compared with mismatches (P<.05) but similar to the other groups. During dobutamine infusion, glucose extraction declined in the normal volunteers (0.19±0.08 µmol/mL; P<.05) and in normal remote regions (0.28±0.08 µmol/mL; P<.05) but remained unchanged in all dysfunctional regions: abnormal remote regions (0.61±0.25 µmol/mL; P=NS versus baseline), mismatches (0.95±0.40 µmol/mL; P=NS versus baseline), and matches (0.70±0.54 µmol/mL; P=NS versus baseline). Thus, glucose extraction in regions with normal function decreased with dobutamine but not in dysfunctional myocardium.
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Discussion |
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In this study in 19 chronic CAD patients, low-dose dobutamine did not significantly alter wall motion in myocardial regions with PET blood flow metabolism matches but improved regional wall motion in the majority of mismatch regions. This improvement in contractile function was associated with an increase in regional MBF and glucose utilization. In remote myocardium, glucose utilization remained on average unchanged during dobutamine infusion, whereas glucose extraction declined. Despite this decrease, extraction of glucose remained constant in mismatch regions. Last, 11 of the 19 patients revealed remote myocardium with apparently normal MBF but impaired wall motion. This type of remote myocardium revealed an attenuated wall motion and flow response to dobutamine.
Effects of Dobutamine Stimulation on Hypoperfused Myocardial Regions
While wall motion failed to improve with dobutamine in match regions, it improved in the majority (70%) of mismatch regions. Despite a possible bias in patient selection in favor of such improvement, the findings nevertheless appear consistent with those reported previously.5 6 Yet, there may be important differences. In one study in early postinfarction patients,5 the excellent agreement between stress echocardiographic and PET findings might be attributed to the fact that most if not all regions were "postischemic" or "stunned." This may differ from chronic states of regional dysfunction and hypoperfusion, often referred to as "hibernating,"1 in which some segments, as in the current study, cannot improve wall motion in response to dobutamine. Conceivably, this might be due to an abundance of "degenerated" myocytes with loss of myofibrils in chronically dysfunctional myocardium.18 19 20 Excessive scar tissue formation in irreversibly dysfunctional myocardium may, on the other hand, explain the absent wall motion response to dobutamine in PET match regions.
Previous studies with PET reported a loss or a marked reduction of myocardial flow reserve by intravenous dipyridamole in flow metabolism match and mismatch regions.3 18 In the current study, baseline MBF was reduced by 53±16% in match regions and by 26±11% in mismatch regions relative to remote myocardium. The absence of a flow response in match regions in the current study agrees with earlier observations.3 Yet, in contrast to the hypothesis to be tested in this study, low-dose dobutamine raised MBF in mismatch regions. Though less in absolute units, its percentage of increase approached that in normal or abnormal remote myocardial regions.
The flow responses to dipyridamole in an earlier study3 and to dobutamine in the current study varied considerably between patients and ranged from 10% to 72% for dobutamine. However, only the flow response to dobutamine achieved statistical significance. Because PET measures only transmural blood flow, a modest increase in one layer of the myocardium may have been offset by a "coronary steal"21 –related decline in another layer so that on average, transmural blood flow remained unchanged, declined slightly, or increased modestly. Different from dipyridamole, flow responses to dobutamine are mediated by an increase in oxygen demand due to increased contractile work reflected in the current study by the improvement in wall motion in mismatch segments. Such dobutamine-mediated increases in oxygen demand and consequently in flow may be distributed heterogeneously across the LV wall. The net result represents an increase albeit of variable magnitude.
The comparable percent flow increases in mismatch and in remote myocardium remain unexplained. These comparable responses argue against a flow limitation as, for example, due to coronary stenosis. Because flow increased only modestly, coronary stenoses were unlikely to exert a limiting effect. Varying fractions of scar tissue coexisting with degenerated myocytes and normal myocytes constitute myocardium with flow metabolism mismatches.18 19 Because of the previously reported inverse correlation between resting blood flow and the percent scar tissue,19 20 the residual blood flow at baseline then corresponds to the sum of normal and degenerated myocytes. If dobutamine enhances oxygen demand in the tissue fraction with preserved myocytes as much as in the remote myocardium, it might explain the comparable percentage of increases in flow. Various degrees of admixture of abnormal myocytes may account for the observed interindividual variability in the flow responses to dobutamine.
As another interesting observation, the rates of MRGlc increased with dobutamine in mismatch regions and glucose extraction remained unchanged but declined in normal remote myocardium, while glucose utilization rates remained unchanged. Several factors may account for this selective increase in or the persistence of glucose utilization. First, if the flow response failed to match fully the increased demand due to higher contractile work, the affected myocardium may have shifted to the more oxygen-efficient glucose. Second, if the increase in demand markedly exceeded the flow supply, mild ischemia with an accelerated glycolysis may have ensued.22 23 Although blood flow and wall motion increased, it is uncertain whether the normal coupling between flow and demand was maintained during the dobutamine infusion because wall motion was evaluated only qualitatively. Third, glucose metabolism in mismatch regions participates only incompletely in the normal response of substrate metabolism to changes in circulating substrate levels.24 Thus, glucose extraction may have remained constant despite the decline in remote myocardium. Last, it is possible that dobutamine selectively enhanced glucose transport in functionally compromised myocytes and/or degenerated myocytes associated with possibly altered glucose transporters and altered responses to adrenergic stimulation.25
Effects of Dobutamine on Normal and Remote Myocardium
In the normal volunteers, blood flow increased in proportion to the dobutamine-induced increase in cardiac work. Consistent with previous observations,14 26 blood flow indeed remained correlated with the RPP. Dobutamine exerts its effect through ß1-receptor stimulation, which enhances heart rate and contractility27 ; both are major determinants of myocardial oxygen demand, which in turn regulates MBF. Stimulation of ß1-receptors activates lipolysis, which appears to be responsible for the increase in circulating free fatty acid levels, as observed in the normal volunteers. Together with the changes in plasma substrate levels, dobutamine thus lowered the rates of MRGlc by 49±28%; such decrease has been demonstrated previously with 18F-deoxyglucose in animal and human investigations in response to catecholamine administration28 or dietary manipulation of plasma substrate levels.8 24
In the patients, the responses to low-dose dobutamine were attenuated. On average, blood flow in remote myocardium increased less than in the normal volunteers, whereas MRGlc did not change from baseline to dobutamine. Different from the normal volunteers, circulating free fatty acid levels in the patients at baseline tended to be higher than in normal volunteers, conceivably due to increased catecholamine levels known to be present in patients with impaired LV performance. Chronically elevated plasma catecholamine levels may prompt a downregulation of ß-receptors, which might account for the attenuated response to low-dose dobutamine.29
Most striking was the observation of two types of remote myocardium with normal blood flows at rest. One type exhibited normal wall motion at rest and a normal flow response to dobutamine, whereas in the second type, wall motion at baseline was reduced yet improved with dobutamine and flow responses were markedly diminished. The more severely reduced LV ejection fractions in the patients with abnormal remote myocardium suggest that this type may indeed represent remodeled myocardium.30 31 32 Ventricular remodeling can progressively develop after an acute myocardial infarction.33 34 Remote myocardium in ischemic cardiomyopathy exhibits diffuse interstitial fibrosis together with ultrastructural changes of cardiac myofilaments.35 These structural changes might account for the reduced contractile function; they also imply a decrease in resting blood flow per unit of myocardial tissue. Yet, such decrease may be offset by an increase in flow due to the increased wall stress as demonstrated in dilated cardiomyopathy.36 This might explain why resting blood flow in remote myocardium of these patients was similar to that in patients with normal remote myocardium or, further, to that in the normal volunteers.
The mechanism underlying the attenuated flow response to dobutamine in abnormal remote myocardium remains uncertain. Although some abnormal remote myocardial regions in the current study were supplied by diseased coronary arteries, this was also the case for normal remote myocardium with normal flow responses. Furthermore, even in normal myocardium, the flow responses were relatively modest and thus were unlikely to be limited by coronary stenoses. The absence of new, dobutamine-induced flow defects appears to support this explanation. A diminished response in contractile function was more likely because of the structural alterations of myocytes and interstitium combined with a reduced responsiveness to dobutamine as a result of downregulated ß-receptors,29 35 which could explain the reduced response in blood flow.
Study Limitations
One limitation relates to patient selection. To recruit patients with a higher likelihood of flow metabolism mismatches, 6 of the 10 patients with mismatch regions were enlisted because of a positive dobutamine echocardiogram. This may have contributed to the generally good agreement between findings on dobutamine stress echocardiography and PET for the identification of viable myocardium, although the degree of correlation appears to be consistent with that reported previously.5 6 Also, the normal control subjects in this study and the patients are not age-matched. However, the response to dobutamine in RPP and in MBF appears to be independent of age.37 38
As another potential shortcoming, wall motion was not reevaluated with echocardiography immediately after the 1-hour-long infusion of dobutamine for the 18F-deoxyglucose study. Therefore, it remains uncertain whether wall motion in hypoperfused myocardial segments remained constant during prolonged exposure to dobutamine. Although it is conceivable that the prolonged exposure to dobutamine stress could have caused subclinical ischemia with deterioration of wall motion, none of the patients in this study revealed clinical signs of ischemia such as angina, ECG changes, or hypotension during the administration of dobutamine. This limitation extends also to the lack of measurements of blood flow and glucose utilization toward the end of the 
1-hour dobutamine infusion. Because most of the 18F-deoxyglucose becomes trapped in myocardium within the first 10 minutes after tracer injection, the metabolic information pertains mostly to the early response to ß-receptor stimulation. The results, therefore, do not indicate whether changes in regional glucose utilization as well as in blood flow occurred over the time of the dobutamine infusion.
Furthermore, the long time interval between coronary angiography and the PET study limits the value of correlating angiographic findings to wall motion in remote myocardium at the time of the PET study. However, normal wall motion at rest and during dobutamine, normal stress electrocardiography, absence of ischemic symptoms, and normal blood flow by semiquantitative analysis in these regions argue against the presence of CAD that would have affected the moderate flow responses to the low-dose dobutamine. However, these findings do not exclude the presence of coronary stenoses that might have been flow-limiting had a more potent vasodilator been used. Such stenoses also might have resulted in a chronic dysfunction and been associated with morphological changes, as previously postulated as one form of repetitive stunning.18
Four patients had diabetes and two had left bundle branch block. While these abnormalities could have affected the results, no significant differences between these and the remaining patients were noted regarding blood flow, substrate metabolism, and responses to dobutamine. Thus, inclusion of these patients did not significantly alter the overall results and its conclusions.
Conclusions and Clinical Implications
The majority of dysfunctional and hypoperfused myocardial regions considered viable by blood flow metabolism imaging on PET improved contractile function in response to low-dose dobutamine stimulation. This improvement was associated with an increase in regional blood flow. Whether the flow increases adequately matched the increases in contractile work remains uncertain. The selective regional increase in glucose utilization might imply the occurrence of acute ischemia during dobutamine infusion, which, if repeated frequently, might result in a progressive loss of "viability," necrosis, and scar tissue formation. Alternatively, the selective increase and glucose utilization might reflect regional alterations in ß-receptor function and densities or altered substrate usage by degenerated myocytes. Of interest is the observation of remote myocardium with diffusely impaired wall motion yet apparently normal blood flow. It might represent remodeled LV myocardium because it was present in the patients with the most severely reduced LV function. Both blood flow and wall motion improved in response to dobutamine, although these responses were attenuated relative to those in normal myocardium. The existence of such remodeled myocardium thus may contribute to the reportedly excellent agreement of viability detection by dobutamine echocardiography and PET metabolic imaging. Yet, there is doubt whether such remodeled myocardium will improve contractile function in response to revascularization.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by the Director of the Office of Energy Research, Office of Health and Environmental Research, Washington, DC, by Research Grants HL-29845 and HL-33177, National Institutes of Health, Bethesda, Md, and by an Investigative Group Award by the Greater Los Angeles Affiliate of the American Heart Association, Los Angeles, Calif. Dr Sun is the recipient of a stipend of the Swiss National Science Foundation. The authors wish to thank Ron Sumida, Larry Pang, Francine Aguilar, Der-Jenn Liu, and Marc Hulgan for their excellent technical assistance, the staff of the Medical Cyclotron at UCLA for providing the isotopes, Deborah Dorsey and the staff of the Charles and Mary Kurlan Heart Center for their assistance, Diane Martin, who prepared the tables and figures, and Eileen Rosenfeld for her assistance in preparing the manuscript.
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Footnotes |
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Presented in part at the 43rd Annual Scientific Session of the American College of Cardiology, Atlanta, Ga, March 1994.
Received April 9, 1996; revision received September 9, 1996; accepted September 12, 1996.
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References |
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