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Circulation. 1997;96:2884-2891

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(Circulation. 1997;96:2884-2891.)
© 1997 American Heart Association, Inc.

Articles

Dependency of Contractile Reserve on Myocardial Blood Flow

Implications for the Assessment of Myocardial Viability With Dobutamine Stress Echocardiography

Hans H. Lee, MD; Victor G. Dávila-Román, MD; Philip A. Ludbrook, MBBS; Michael Courtois, MA; John F. Walsh, MD; Deborah A. Delano, BS; Patricia J. Rubin, MD; ; Robert J. Gropler, MD

From the Cardiovascular Division, Department of Internal Medicine (H.H.L., V.G.D.-R., P.A.L., M.C., J.F.W., P.J.R., R.J.G.) and the Division of Nuclear Medicine, Edward Mallinckrodt Institute of Radiology (D.A.D., R.J.G.), Washington University School of Medicine, St Louis, Mo.

Correspondence to Robert J. Gropler, MD, Mallinckrodt Institute of Radiology, 510 S Kingshighway Blvd, St Louis, MO 63110. E-mail gropler{at}mirlink.wustl.edu


*    Abstract
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 *Abstract
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Background Contractile reserve, improvement in contractile function during inotropic stimulation, is a proposed marker of viable myocardium. This study was designed to address, in patients with left ventricular dysfunction due to chronic coronary artery disease, whether contractile reserve depends on myocardial blood flow.

Methods and Results We studied 19 patients, at rest and during dobutamine, with 2D echocardiography for regional mechanical function and PET for regional myocardial blood flow ([15O]water) and oxygen consumption ([11C]acetate). Of 166 myocardial segments, 21 had normal systolic function, 56 were dysfunctional but contractile reserve–positive, and 89 were dysfunctional and contractile reserve–negative. Myocardial blood flow at rest was lower in contractile reserve–negative (0.41±0.18 mL · g-1 · min-1) than in contractile reserve–positive (0.50±0.22 mL · g-1 · min-1) and normal segments (0.55±0.20 mL · g-1 · min-1, P<.009). After dobutamine infusion, blood flow increased less in contractile reserve–negative (0.63±0.38 mL · g-1 · min-1) than in contractile reserve–positive (1.28±0.65 mL · g-1 · min-1) and normal segments (1.93±0.83 mL · g-1 · min-1, P<.0001). Likewise, myocardial oxygen consumption was lower at rest in contractile reserve–negative (clearance rate of [11C]acetate, 0.043±0.012 min-1) than in contractile reserve–positive (0.048±0.01 min-1) and normal segments (0.058±0.008 min-1, P<.02). Myocardial oxygen consumption with dobutamine increased less in contractile reserve–negative (0.060±0.013 min-1) than in contractile reserve–positive (0.077±0.016 min-1) and normal segments (0.092±0.024 min-1, P<.0001). Of segments defined as viable by PET, 54% were contractile reserve–negative and exhibited lower blood flow with dobutamine (0.72±0.36 mL · g-1 · min-1) than with viable, contractile reserve–positive segments (1.29±0.70 mL · g-1 · min-1, P<.0001).

Conclusions Contractile reserve depends, in part, on the level of myocardial blood flow at rest and during inotropic stimulation.


Key Words: tomography • myocardial contraction • echocardiography • coronary disease


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowResults
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Reversible left ventricular contractile dysfunction secondary to coronary artery disease has been well described.1 2 3 The presence of reversibly dysfunctional, or viable, myocardium has been used to determine the prognosis and treatment for patients with left ventricular dysfunction secondary to coronary artery disease.4 5 Several noninvasive imaging methods have subsequently been applied to differentiate viable from nonviable myocardium. These include 201Tl scintigraphy,6 PET with [18F]fluorodeoxyglucose7 or [11C]acetate,8 and dobutamine stress echocardiography.9 10 With dobutamine stress echocardiography, dysfunctional segments are identified as viable if they exhibit improvement in contractile function during inotropic stimulation, a phenomenon known as myocardial contractile reserve.11

Results of studies in experimental animals, however, suggest that contractile reserve is dependent on the level of myocardial blood flow at rest and during inotropic stimulation.12 13 14 15 The flow dependency of the contractile reserve phenomenon has important implications regarding the use of dobutamine stress echocardiography to assess myocardial viability, particularly when myocardial blood flow is reduced. It has been speculated but not yet proved that an impairment in myocardial blood flow may explain the lower negative predictive value of dobutamine stress echocardiography to detect viable myocardium in certain clinical scenarios.16 Accordingly, the purpose of this study was to examine in humans the extent to which the capacity of dysfunctional myocardium to exhibit contractile reserve is dependent on the level of myocardial perfusion at rest and during inotropic stimulation.


*    Methods
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 *Methods
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Study Population
The study was approved by the Human Studies and the Radioactive Drug Research committees at the Washington University School of Medicine. All patients provided informed written consent before enrollment. Patients were screened for left ventricular contractile dysfunction with two-dimensional (2D) echocardiography and for coronary artery disease with coronary arteriography. Nineteen patients (17 men and 2 women; mean age, 60±8 years) were found to have left ventricular contractile dysfunction due to chronic coronary artery disease (ie, the severity of left ventricular dysfunction was concordant with the extent of coronary artery disease). Patients were excluded if they had clinical evidence of active or recent (<6 months) myocardial ischemia (eg, unstable angina, myocardial infarction, or pulmonary edema). The majority of patients had moderate-to-severe left ventricular dysfunction at rest (mean ejection fraction, 26±7%), with 15 of 19 patients having global ejection fractions estimated by 2D echocardiography at <25%. Eighteen of 19 patients had multivessel coronary artery disease as determined by coronary arteriography: one vessel (n=1), two vessel (n=2), and three vessel (n=16). Thirteen patients had suffered a remote myocardial infarction, and 12 had undergone previous coronary revascularization with either coronary artery bypass grafting (n=7) or percutaneous transluminal coronary angioplasty (n=5). ß-Blocker therapy was withheld for at least 24 hours before the study.

Imaging Protocol
The imaging protocol is outlined in Fig 1Down. Under resting conditions, patients underwent rest 2D echocardiography (Hewlett-Packard Sonos 1500) in the standard imaging planes (parasternal long- and short-axis, apical two- and four-chamber views) to measure regional contractile function. This was followed by a PET scan (SP-3000E, PETT Electronics) to measure regional myocardial blood flow and myocardial oxygen consumption. A 2-minute scan, obtained with a rotating 68Ge/68Ga sector source, was acquired and reconstructed to verify proper positioning. After the positioning scan, a 15-minute transmission scan was performed for generation of attenuation correction factors used in emission-image reconstruction. The PET protocol to measure myocardial blood flow involved inhalation of 40 mCi of [15O]carbon monoxide, with the immediate collection of a 300-second scan, followed by a bolus of 0.40 mCi/kg IV of [15O]water, with the immediate collection of a 150-second dynamic scan. To measure regional myocardial oxygen consumption, a bolus of 0.40 mCi/kg IV of [11C]acetate was given, followed by a 30-minute dynamic scan to determine [11C]acetate myocardial kinetics. After the rest studies, dobutamine (5, 10, 15, and 20 µg · kg-1 · min-1 IV) was infused during continuous monitoring of blood pressure, heart rate, and regional contractile function (by echocardiography) until maximal contractile improvement was observed or the maximal dose of dobutamine (20 µg · kg-1 · min-1) was reached. Dobutamine infusion was stopped if the patient developed signs or symptoms of myocardial ischemia, significant arrhythmias, and/or symptomatic hypotension. If a decline in regional function was observed, the dose of dobutamine was decreased to the previous level, and regional function was reassessed. At the optimal or peak dose of dobutamine, repeat measurements of myocardial blood flow and oxygen consumption by PET were made. 2D echocardiography was performed at the end of the study (with the patient still on dobutamine) to ensure that myocardial ischemia (defined as a decline in regional wall motion) had not occurred. The echocardiographic images were stored in a cine-loop, digital quad screen format (Tomtec Freeland Systems) for side-by-side comparison of the rest and dobutamine stress images.



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  		Figure 1. Imaging protocol. Under resting conditions, evaluation of regional left ventricular function was performed with 2D echocardiography, followed by measurements of regional myocardial blood flow (MBF) and regional myocardial oxygen consumption (MVO2) with PET. Echocardiography and PET were repeated during dobutamine infusion. Another echocardiogram was obtained at end of study to assess for ischemia.

Image Analysis
Left ventricular segment model. The left ventricle was analyzed by use of an 11-segment model adapted from the American Society of Echocardiography recommendations to allow image registration with the PET images (Fig 2Down).17 Several steps were taken to minimize potential errors due to misalignment of the PET and echocardiographic images. First, all PET images were reformatted into short-axis, horizontal long-axis, and vertical long-axis views, thus allowing direct region-to-region comparison with the corresponding short-axis, apical four-chamber, and apical two-chamber echocardiographic views. Second, PET measurements were averaged over several midventricular slices to obtain a representative sample of the corresponding echocardiographic imaging plane. Finally, only large regions of interest were analyzed, as previously reported.8 The left ventricular septum was not included in our analysis because a significant proportion of our patients had previous coronary artery bypass graft surgery causing paradoxical septal motion, which leads to difficulty in analysis of this region. Myocardial segments were included in the final analysis only if all three physiological parameters (contractile function, myocardial blood flow, and myocardial oxygen consumption) could be quantified accurately.



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  		Figure 2. Left ventricular segment model. Echocardiographic and PET data were analyzed by use of same model, allowing direct region-to-region comparison of myocardial segments. Septum was not analyzed because of difficulties with measurements of myocardial blood flow in this segment.

Echocardiography. Regional contractile function was graded visually, and each myocardial segment was assigned a wall motion score according to a modification of the recommendations of the American Society of Echocardiography, where 1=normal (or hyperdynamic), 1.5=mild hypokinesis, 2=hypokinesis, 2.5=severe hypokinesis, 3=akinesis, and 4=dyskinesis.17 Left ventricular segments with a baseline wall motion score of <1.5 were defined as normal; those with a baseline wall motion score of >=2.0 were defined as dysfunctional. During inotropic stimulation, dysfunctional segments in which contractile function improved by at least one full grade (improvement in wall motion score >=1.0) were classified as contractile reserve–positive. Segments with improvements in wall motion score of less than one grade were classified as contractile reserve–negative. All studies were reviewed independently by two experienced echocardiographers who were blinded to the clinical and PET data. Interobserver concordance was 91%. Discrepancies in wall motion score between the two observers were settled by consensus, and in no case was the disagreement greater than a 0.5 grade. One observer reviewed all the studies twice, at least 2 weeks apart, with an intraobserver concordance of 94%.

PET. Regional myocardial blood flow was quantified by use of a parameter optimization method developed and validated previously at our institution.18 19 20 To permit better quantification at very low flow rates, the partial volume correction factor within this algorithm was fixed to a value calculated independently based on the transmission and [15O]carbon monoxide scans.21 Myocardial oxygen consumption was quantified from the myocardial turnover rate constant of acetate, which reflects the rate of clearance of 11C activity from myocardium after the administration of [11C]acetate and which correlates closely with myocardial oxygen consumption measured directly both in experimental animals and in humans.22 23 24 In addition, the perfusable-tissue index for each segment was calculated as the ratio of the partial-volume correction (determined with the parameter-optimization method) divided by the extravascular tissue density (determined from the transmission scan).25 The perfusable-tissue index has been shown recently by our group to reflect heterogeneity of perfusion across the myocardium, because it is a function of both intensity and transmural distribution of blood flow.25 Therefore, at a given level of transmural blood flow, if heterogeneity of perfusion is high, as in subendocardial infarction, perfusable-tissue index values are low (typically <0.6), and if heterogeneity is low (ie, flow is homogeneous), perfusable-tissue index values are high (approaching 1.0).

Coronary angiography. The extent of coronary artery disease was determined in patients (n=9) who had undergone cardiac catheterization within 6 months of this study but who had not undergone previous coronary artery bypass graft surgery (because of difficulty in determining whether blood flow to a myocardial segment is supplied by the native vessel or the bypass graft). An experienced interventional cardiologist who was blinded to the clinical, PET, and echocardiographic data measured the percent reduction in coronary artery diameter with standard caliper technique. The coronary artery distribution was correlated to the PET and echocardiographic regions of interest by a scheme described by Bourdillon et al.26

Statistical Analysis
Continuous data are presented as mean±SD. Comparison between values for segments at rest and on dobutamine was performed by paired t test. Comparisons between normal, contractile reserve–positive, and contractile reserve–negative segments were performed by ANOVA with appropriate post hoc testing (Bonferroni/Dunn). A statistically significant difference was considered to be present when P<.05.


*    Results
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 *Results
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Segmental Analysis of Contractile Function
Eighteen of the 19 patients completed the imaging protocol. One patient completed the rest PET and the rest and dobutamine stress echocardiograms, but was unable to undergo the dobutamine PET because of symptomatic hypotension; the data from this rest study were included.

Rest images of 209 myocardial segments were potentially available. Of these, 166 segments were of adequate technical quality for assessment of all three measurements of interest: contractile function, myocardial blood flow, and myocardial oxygen consumption. PET images of 43 segments were excluded because of poor quality (ie, low count statistics, myocardium out of the field of view, or patient movement between scans). Because the dobutamine stress data were not available in 1 patient and because of technical considerations in other segments, images of 137 segments during dobutamine infusion were adequate for analysis. An average of 8.7±1.5 segments per patient were analyzed (range, 6 to 11 segments per patient).

Of the 166 rest myocardial segments, 21 (from 5 patients) showed normal contractile function, 56 (from 14 patients) were dysfunctional but contractile reserve–positive, and 89 (from 19 patients) were dysfunctional and contractile reserve–negative. Fifteen of the 19 patients had at least two different types of myocardial segments; 4 patients had only contractile reserve–negative segments. Contractile dysfunction at rest was, by definition, least severe in the normal segments (1.1±0.2). The contractile reserve–negative segments had worse contractile function at rest (2.7±0.4) than the contractile reserve–positive segments (2.3±0.3, P<.0001). By definition, contractile function improved in the contractile reserve–positive myocardial segments during the infusion of dobutamine (wall motion score on dobutamine, 1.2±0.3).

The dobutamine dose at which the PET study was performed was similar in normal and contractile reserve–negative segments (11.7±2.9 µg · kg-1 · min-1 and 11.0±4.6 µg · kg-1 · min-1, respectively, P=NS) but was higher in contractile reserve–positive segments (14.1±4.5 µg · kg-1 · min-1, P<.0001 versus contractile reserve–negative segments).

Measurements of Myocardial Blood Flow
Myocardial blood flow measured at rest and during dobutamine infusion and the absolute change in myocardial blood flow for each class of myocardial segments are shown in Fig 3Down. Myocardial blood flow at rest was lower in contractile reserve–negative segments (0.41±0.18 mL · g-1 · min-1) than in either contractile reserve–positive (0.50±0.22 mL · g-1 · min-1) or normal segments (0.55±0.20 mL · g-1 · min-1, P<.009). During dobutamine infusion, myocardial blood flow increased in all three groups of segments (P<.0001). However, the level of myocardial blood flow during inotropic stimulation remained lower in the contractile reserve–negative (0.63±0.38 mL · g-1 · min-1) than in contractile reserve–positive segments (1.28±0.65 mL · g-1 · min-1) or normal segments (1.93±0.83 mL · g-1 · min-1, P<.0001). Myocardial blood flow during dobutamine in contractile reserve–positive segments was also less than in normal segments (P<.0001). The increase in myocardial blood flow from rest to dobutamine was blunted in contractile reserve–negative segments (0.25±0.35 mL · g-1 · min-1) compared with contractile reserve–positive (0.80±0.59 mL · g-1 · min-1) and normal segments (1.38±0.86 mL · g-1 · min-1, P<.0001). The increase in blood flow was also less in contractile reserve–positive segments than in normal segments (P<.0001). Thus, in myocardial segments that are dysfunctional at rest, the presence of contractile reserve is associated with higher levels of myocardial blood flow at rest and during inotropic stimulation.



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  		Figure 3. Top, MBF (mL · g-1 · min-1) at rest and during dobutamine for normal (NL), contractile reserve–positive (CR+), and contractile reserve–negative (CR-) segments. MBF at rest was lower in CR- segments than in either CR+ or NL segments. During dobutamine, MBF increased in all three segment groups (P<.0001) but remained lower in CR- segments than in CR+ or NL segments. MBF with dobutamine was less in CR+ segments than in NL segments. Bottom, Change in MBF from rest to on dobutamine (MBFdob-MBFrest). Change in MBF was less in CR- segments than in CR+ or NL segments and less in CR+ segments than NL segments. Abbreviations as in Fig 1Up.

Measurements of Myocardial Oxygen Consumption
Measurements of myocardial oxygen consumption at rest and on dobutamine and the absolute change in myocardial oxygen consumption for each group of myocardial segments are shown in Fig 4Down. Commensurate with the reduction in blood flow, myocardial oxygen consumption at rest was lower in the contractile reserve–negative segments (0.043±0.012 min-1) than in either contractile reserve–positive (0.048±0.01 min-1) or normal segments (0.058±0.008 min-1, P<.02). During dobutamine infusion, myocardial oxygen consumption increased in all three groups (P<.0001). The level of myocardial oxygen consumption on dobutamine was lower in contractile reserve–negative segments (0.060±0.013 min-1) than in contractile reserve–positive (0.077±0.016 min-1) or normal segments (0.092±0.024 min-1, P<.0001). Myocardial oxygen consumption on dobutamine was also less in contractile reserve–positive compared with normal segments (P=.0007). The increase in myocardial oxygen consumption from rest to dobutamine was blunted in contractile reserve–negative segments (0.018±0.011 min-1) compared with contractile reserve–positive (0.030±0.014 min-1) and normal segments (0.034±0.021 min-1, P<.0001). Thus, as with blood flow, the presence of contractile reserve is associated with higher levels of myocardial oxygen consumption at rest and during dobutamine infusion.



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  		Figure 4. Top, MVO2 (min-1) at rest and during dobutamine for NL, CR+, and CR- segments. MVO2 at rest was lower in CR- segments than in CR+ or NL segments. With dobutamine, MVO2 increased in all three groups (P<.0001) but remained lower in CR- segments than in CR+ or NL segments. Also, MVO2 on dobutamine in CR+ segments was less than that in NL segments. Bottom, Change in MVO2 from rest to on dobutamine (MVO2dob-MVO2rest). As with flow, augmentation in MVO2 was less in CR- segments than in NL and CR+ segments. Abbreviations as in previous figures.

Measurements of Percent Reduction in Coronary Artery Diameter
Percent reduction in diameter for the coronary arteries supplying each group of myocardial segments is shown in Fig 5Down. The percent reduction in coronary artery diameter was more severe in contractile reserve–negative segments (88%±24%) than in contractile reserve–positive (67%±38%, P=.0056) or normal segments (24%±39%, P<.0001). Also, the percent reduction in coronary artery diameter was more severe in contractile reserve–positive than normal segments (P=.0004). Therefore, in concordance with the blood flow measurements, the absence of contractile reserve is associated with more severe coronary artery stenosis.



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  		Figure 5. Mean percent reduction in coronary artery diameter for NL, CR+, and CR- segments. Percent reduction in coronary artery diameter was more severe in CR- than CR+ or NL segments and in CR+ than NL segments. Abbreviations as in previous figures.

Myocardial Blood Flow, Contractile Reserve, and Myocardial Viability
To determine the extent to which differing admixtures of viable and nonviable myocardium may have contributed to the relationship between myocardial blood flow and contractile reserve, we measured these parameters in dysfunctional segments classified as viable or nonviable on the basis of rest levels of myocardial oxygen consumption as measured by PET, according to previously validated criteria (TableDown).8 Of the 102 segments classified as viable, 55 (54%) were contractile reserve–negative. These segments exhibited lower levels of myocardial blood flow during dobutamine and a smaller increase in myocardial blood flow from rest than that measured in viable, contractile reserve–positive segments (P<.0001). Of the 43 segments classified as nonviable by PET, 34 (79%) were contractile reserve–negative. In these segments, the level of myocardial blood flow at rest and during dobutamine and the absolute increase in myocardial blood flow were less than observed in nonviable, contractile reserve–positive segments (P<.002). Thus, in the presence of equivalent levels of myocardial oxidative metabolism, contractile reserve is still associated with higher levels of blood flow, making it unlikely that differences in the extent of viable and nonviable tissue alone can fully account for the observed relationship between the level of blood flow and contractile reserve.


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  		Table 1. Contractile Reserve vs PET-Acetate Viability

Measurements of Transmural Flow Heterogeneity
Measurements of rest perfusable-tissue index normalized to rest myocardial blood flow are shown in Fig 6Down for contractile reserve–positive and contractile reserve–negative segments. Because the perfusable-tissue index is sensitive to the absolute level of blood flow, the normalized perfusable-tissue index, rather than the absolute perfusable-tissue index, is more useful for comparing transmural flow heterogeneity between different myocardial segments. The normalized perfusable-tissue index was similar at rest in contractile reserve–positive (1.71±0.62) and contractile reserve–negative segments (1.78±0.94, P=NS), suggesting that the degree of flow heterogeneity between these segments was similar.



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  		Figure 6. Average perfusable-tissue index (PTI) normalized to myocardial blood flow for CR+ and CR- segments at rest. Normalized PTI at rest was similar in CR+ and CR- segments, suggesting similar transmural flow heterogeneity between these segments. Abbreviations as in previous figures.


*    Discussion
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Reversible contractile dysfunction is thought to result from repetitive or prolonged ischemia (stunning) or from chronic hypoperfusion (hibernation).2 27 28 Differentiation of reversibly (viable) from irreversibly (non-viable) dysfunctional myocardium has been used to determine both prognosis and treatment for patients with ischemic cardiomyopathy. Improvement in contractile function of dysfunctional myocardium during inotropic stimulation, or contractile reserve, has been proposed as a marker of myocardial viability. The results of the present study demonstrate that in patients with moderate-to-severe left ventricular dysfunction due to chronic coronary artery disease, the capacity to exhibit contractile reserve probably depends on the level of myocardial blood flow both at rest and during inotropic stimulation.

Myocardial Blood Flow and Contractile Function
The dependence of contractile function on the level of myocardial blood flow at rest is well established.29 30 The importance of myocardial blood flow on the augmentation of contractile function with inotropic stimulation has also been shown in several animal models. McGillem et al12 studied acute ischemia in dogs and demonstrated that dysfunctional myocardial segments supplied by coronary arteries with the greatest stenoses had the smallest augmentation in coronary flow during dobutamine infusion (10 µg · kg-1 · min-1) and lacked contractile reserve. Sklenar et al13 showed in dogs subjected to acute ischemia and reperfusion that wall thickening during dobutamine correlated with the extent of myocardial necrosis except in segments supplied by totally occluded arteries. In the latter segments, there was no contractile reserve during dobutamine, despite histological evidence of viable myocardium. A more recent study by Sklenar et al14 , also in dogs subjected to acute ischemia and reperfusion, showed that a residual coronary stenosis that limits hyperemic flow will attenuate the contractile reserve response. Chen et al15 studied the response to low- and high-dose dobutamine in porcine models of acute ischemia and short-term hibernation (1.5 and 24 hours, respectively). They demonstrated that at low doses of dobutamine (4.5±2.2 µg · kg-1 · min-1), coronary flow increased and contractile function improved, but at higher doses (12.6±4.1 µg · kg-1 · min-1), coronary flow was not augmented and contractile function deteriorated. These experiments provide compelling evidence for a flow dependency of the contractile reserve phenomenon in acute and subacute myocardial ischemia. The results of our study suggest that a similar relationship between the level of myocardial blood flow and contractile reserve is present in humans with chronic coronary artery disease.

Previous work in humans to quantify the relationship between contractile reserve and myocardial blood flow is limited. Severi et al31 used MRI to measure the effects of dobutamine (5 to 40 µg · kg-1 · min-1) on regional contractile function while measuring myocardial blood flow with PET and [15O]water in patients with acute and chronic coronary artery disease. They showed that myocardial segments exhibiting normal contractile augmentation during dobutamine exhibited greater increases in myocardial blood flow than segments in which contractile function worsened with inotropic stimulation. This study differs from our own because Severi et al looked at worsening wall motion with dobutamine in patients with normal or mildly decreased left ventricular function, whereas we studied improvement in wall motion with dobutamine in patients with moderate-to-severe left ventricular dysfunction. Sawada et al32 showed, in patients with primarily chronic coronary artery disease, that contractile reserve occurred more commonly when rest perfusion (measured by [13N]ammonia and PET) was normal than when it was reduced. This study, although similar to our own, did not include quantitative measurements of blood flow, nor did it include measurements of blood flow during dobutamine infusion.

Composition of Dysfunctional Myocardium: Impact on Contractile Reserve
Our data provide evidence for an association between myocardial blood flow and contractile reserve, but other factors may be important. It is possible that the extent of infarcted tissue within a myocardial segment is a more critical determinant of contractile reserve. We assessed the impact of varying admixtures of viable and nonviable myocardium on the association between contractile reserve and the level of blood flow in two ways. First, we examined the association between contractile reserve and myocardial blood flow in segments classified as viable and nonviable on the basis of the level of myocardial oxygen consumption as measured by PET.8 33 In a similar patient population, we have shown previously that the level of myocardial oxygen consumption can predict improvement in contractile function after coronary revascularization with a positive predictive value of 85% and a negative predictive value of 87%.8 More than half of the segments in the present study identified as viable did not exhibit contractile reserve. These segments exhibited less augmentation of myocardial blood flow during inotropic stimulation than that observed in viable segments with contractile reserve. Therefore, given an equivalent extent of metabolically viable myocardium, adequate levels of myocardial blood flow appear to be a prerequisite for the contractile reserve response. Similarly, Iliceto et al34 compared dobutamine stress echocardiography with myocardial contrast echocardiography in humans after acute myocardial infarction and showed that microvascular integrity may be a prerequisite for the presence of contractile reserve. Our data extend the hypothesis that contractile reserve may depend on myocardial blood flow to patients with chronic coronary syndromes.

A second method used to assess the impact of varying admixtures of viable and nonviable myocardium on the association between contractile reserve and the level of blood flow was to estimate heterogeneity in the transmural distribution of blood flow in each myocardial segment. It has been shown that the subendocardium contributes the most to overall systolic thickening and that reductions in subendocardial blood flow have the greatest impact on segmental contractile function.35 36 Therefore, it is possible that in the contractile reserve–negative segments, the presence of subendocardial infarction accounted for the lower levels of myocardial blood flow observed. Although the limited spatial resolution of PET images precludes direct quantification of myocardial blood flow within specific layers of the myocardium, the perfusable-tissue index calculated from the PET images provides an indirect measure of the heterogeneity of transmural blood flow. The rest perfusable-tissue index normalized to the level of rest myocardial blood flow was similar in contractile reserve–positive and contractile reserve–negative segments, suggesting that flow heterogeneity at rest was similar in this group of segments. Therefore, the comparable values of normalized perfusable-tissue index in these segments, taken in sum with differing levels of blood flow in the contractile reserve–negative and contractile reserve–positive segments, despite similar levels of viable myocardium, make it unlikely that the admixture of viable and nonviable myocardial tissue is the sole determinant of contractile reserve in this study.

Other Determinants of Contractile Reserve
After myocardial infarction, contractile function of a myocardial segment can be affected by the contractile function of adjacent segments. Noninfarcted segments adjacent to infarcted segments often exhibit abnormalities in circumferential shortening that are due, at least in part, to changes in regional stress-strain relations and/or availability of metabolic substrates.37 38 Therefore, contractile reserve is also likely to depend on the contractile function of adjacent myocardial segments, overall left ventricular geometry, and segmental stress-strain relations.

The increase in myocardial oxygen consumption during dobutamine despite the absence of contractile reserve in myocardial segments with viable tissue by PET may be due to alterations in energy transduction. The oxygen cost of excitation-contraction coupling in patients with coronary artery disease is higher in patients with moderate-to-severe left ventricular dysfunction than in those with normal or mildly decreased systolic function.39 Thus, during inotropic stimulation, some dysfunctional but viable segments may be unable to augment contractile function.

Limitations
It cannot be concluded with certainty that the impaired blood flow response during dobutamine resulted in blunting of contractility as opposed to the reverse scenario. Decreased contractility could account for the impairment in blood flow secondary to decreased oxygen demand. However, the findings of reduced blood flow at rest, more severe coronary artery stenosis, and similar flow heterogeneity in contractile reserve–negative segments are in agreement with results of studies in experimental animals, supporting the primacy of the dependence of contractile reserve on the level of myocardial blood flow.

The dose of dobutamine administered to patients with contractile reserve–positive segments was slightly higher than that given to patients with contractile reserve–negative segments. Patients with a higher proportion of contractile reserve–negative segments may have been more susceptible to ischemia and thus were unable to tolerate higher doses of dobutamine. This difference, however, was small (3.2 µg · kg-1 · min-1) compared with the differences in augmentation of myocardial blood flow and oxygen consumption with dobutamine in the two groups and therefore was not likely to have been the primary determinant of which segments exhibited contractile reserve.

In our study, the severity of systolic dysfunction at rest was greater in the contractile reserve–negative segments than in the contractile reserve–positive segments. This may be secondary to different proportions of infarcted tissue within these segments; however, as discussed, it probably reflects lower levels of myocardial blood flow. Regardless, the difference in wall motion score at rest between the two groups was small (0.4) and unlikely to have been a major determinant of which segments exhibited contractile reserve.

In an attempt to show the dependency of contractile reserve on myocardial blood flow, we used the level of myocardial oxygen consumption to classify viable myocardium. The traditional "gold standard" of myocardial viability is the recovery of contractile function after coronary revascularization. However, the measurement of myocardial oxygen consumption with PET is an accurate marker of functional recovery after coronary revascularization, as shown by our laboratory8 and by others.33 Furthermore, the main focus of this study was not to determine which imaging technique best identified viable myocardium but rather to better elucidate the impact of myocardial blood flow on the contractile reserve response. Clearly, studies designed to determine the relative accuracy of blood flow measurements, contractile reserve, and myocardial metabolism to identify reversibly dysfunctional myocardium would require measurement of these parameters before and after coronary revascularization.

Implications of the Study
The presence of contractile reserve on the dobutamine stress echocardiogram is currently used to detect viable myocardium. It has been shown to be accurate in predicting recovery of function after reperfusion9 10 40 but may have reduced negative predictive value in certain clinical settings.41 42 43 In this study, we have shown the blood flow dependency of the contractile reserve phenomenon. These findings provide a physiological explanation for why some viable myocardial segments in which contractile function fails to improve during inotropic stimulation may ultimately recover function after coronary reperfusion.


*    Acknowledgments
 
This work was supported in part by NIH grants HL-13581, HL-48906, and HL-54361 and by a Minority Scientist Development Award from the American Heart Association, Dallas, Tex, to Dr Dávila-Román. We would like to thank Edward M. Geltman, MD, and Julio E. Pérez, MD, for their thoughtful review of the manuscript.

Received January 9, 1997; revision received June 11, 1997; accepted June 19, 1997.


*    References
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