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Dobutamine Response and Myocardial Infarct Transmurality: Functional Improvement after Coronary Artery Bypass Grafting—Initial Experience¹

¹ From the Departments of Medicine, Cardiovascular Division (C.M.B., S.V., C.M.K.), Health Evaluation Sciences (M.R.C.), and Radiology (J.M.D., C.M.K.), University of Virginia Health System, University of Virginia, Lee St, Box 800170, Charlottesville, VA 22908. Received July 8, 2005; revision requested September 12; revision received October 4; final version accepted October 19. C.M.B. and S.V. supported in part by National Institutes of Health, National Heart, Lung and Blood Institute, T32 HL07355. Address correspondence to C.M.K. (e-mail: ckramer{at}virginia.edu).

	ABSTRACT

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The Investigational Review Board approved the protocol, and all patients provided signed informed consent. The protocol was compliant with HIPAA. The purpose of the study was to prospectively test the hypothesis that addition of low-dose dobutamine and quantification of inotropic reserve in segments with 1%–50% infarct transmurality (IT) would improve the predictive value for functional recovery after revascularization in chronic infarction. Fifteen patients with multivessel coronary artery disease and left ventricular systolic dysfunction were enrolled prior to coronary artery bypass grafting (CABG). Late gadolinium-enhanced cardiac magnetic resonance (MR) imaging was used to assess IT. The percentage of wall thickening was measured with cine cardiac MR imaging at rest and during infusion of 10 (µg · kg^–1)/min dobutamine. Repeat cardiac MR imaging was performed 20 weeks ± 4 (standard error) later. Functional parameters according to segment were compared before and after CABG by using F tests with repeated-measures models. In segments with 1%–50% IT, similar functional recovery was noted in those with 1%–25% or 26%–50% IT. However, in the same segments, those that improved with dobutamine to normal range demonstrated greater improvement in the percentage of wall thickening (22% ± 4) after revascularization than those that did not (9% ± 4) (P < .04). In 1%–50% IT, a normal dobutamine response helps differentiate segments with greater functional recovery after CABG.

© RSNA, 2006

	INTRODUCTION

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To determine the likelihood of functional recovery in dysfunctional myocardium after revascularization in patients with chronic ischemic heart disease, several imaging approaches have been used. Positron emission tomography (PET), as a metabolic marker of viability, has long been considered a reference standard (1). Wall thickness at rest of less than 5.5–6.0 mm at either echocardiography (2) or cardiac magnetic resonance (MR) imaging (3) may be used as a marker of nonviability. Contractile reserve at dobutamine echocardiography (4,5) or low-dose dobutamine cine cardiac MR imaging is predictive of functional recovery (3,6). A positive dobutamine response requires at least 50% viable myocytes in a given segment (7).

Late gadolinium-enhanced cardiac MR imaging has been validated as a technique to assess the amount of nonviable myocardium as a percentage of the transmural extent of a given segment (8) and has been shown to be more sensitive than PET for nontransmural infarction (9). In a study of 50 patients with left ventricular (LV) dysfunction prior to revascularization, infarct transmurality (IT) was associated with the likelihood of functional recovery after revascularization (10). Nearly 80% of segments with no late enhancement recovered function, whereas only 8% of segments with more than 50% IT had improved. In the segments with 1%–50% IT (36% of dysfunctional segments), the predictive value for recovery in a given segment was between 40% and 60%.

Authors of a recent study suggested that low-dose dobutamine cine cardiac MR imaging was more accurate than IT at helping predict recovery after revascularization, especially in segments with 1%–74% IT (11). Some authors raise questions about the receiver operating characteristic analysis used in that particular study and suggest that this issue may not be as clinically relevant because the potential for benefit from revascularization is potentially great in these segments (12). The purpose of our study was to prospectively test the hypothesis that addition of low-dose dobutamine and quantification of inotropic reserve in segments with 1%–50% IT would improve the predictive value for functional recovery after revascularization in chronic infarction.

	MATERIALS AND METHODS

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Patients
Fifteen patients (12 men, three women; mean age, 67 years ± 3) with significant coronary artery disease (>70% stenosis in two or more major epicardial vessels) and ischemic LV dysfunction (ejection fraction <45% at echocardiography or contrast material–enhanced ventriculography) were enrolled prior to planned coronary artery bypass grafting (CABG). The patients were enrolled from March 2002 through September 2003. Clinical characteristics of the patients enrolled are shown in Table 1. Three patients had prior revascularization (two, prior CABG; one, prior stent placement). The investigational review board at our institution approved the protocol, and all patients provided signed informed consent. The protocol was compliant with the Health Insurance Portability and Accountability Act. Exclusion criteria included acute myocardial infarction (within 4 weeks); atrial fibrillation; inability to lie flat; and/or contraindications to cardiac MR imaging, such as the presence of pacemakers or implantable defibrillators.

View larger version (85K): [in this window] [in a new window] [Download PPT slide]   Figure 1: Patient 13. A, Basal short-axis electrocardiographically gated inversion-recovery gradient-echo MR image (repetition time msec/echo time msec, 8/4.3; 30° flip angle) obtained 20 minutes after infusion of gadopentetate dimeglumine prior to CABG. Infarction is seen in inferior and lateral walls (from 2- to 8-o'clock position) that subtends 30% of transmural extent of myocardial wall thickness. Predictive value for recovery in this segment is intermediate on the basis of IT alone. B-G, Short-axis steady-state free precession cine MR series (3.1/1.6, 60° flip angle). B, End-diastolic image before revascularization (ED pre). C, End-diastolic image obtained during infusion of 10 (µg · kg–1)/min of dobutamine (ED dob). D, End-diastolic image 5 months after revascularization (ED post). E, End-systolic image before revascularization (ES pre) demonstrates akinesis of lateral and posterior segments (from 2- to 6-o'clock position, two of six segments). Mean wall thickening in these segments was 5%. F, End-systolic image obtained during infusion of dobutamine (ES dob) demonstrates lack of improvement in the same lateral and posterior segments (mean wall thickening, 6%). Remaining segments show increase in wall thickening with dobutamine. G, End-systolic image after revascularization (ES post) demonstrates no recovery of function in lateral and posterior segments (mean wall thickening, 6%). Remaining segments show improvement with revascularization.

View larger version (85K): [in this window] [in a new window] [Download PPT slide]   Figure 2: Patient 13. A, Apical short-axis electrocardiographically gated inversion-recovery gradient-echo MR image (8/4.3, flip angle 30°) obtained 20 minutes after gadopentetate dimeglumine infusion. Infarction is seen in inferoposterior and lateral walls (from 3- to 8-o'clock position) that subtends 20% of transmural extent of myocardial wall thickness. Predictive value for recovery in this segment is intermediate on the basis of IT alone. B-G, Short-axis steady-state free precession cine MR series (3.1/1.6, 60° flip angle). B, End-diastolic image before revascularization (ED pre). C, End-diastolic image obtained during infusion of 10 (µg · kg–1)/min of dobutamine (ED dob). D, End-diastolic image 5 months after revascularization (ED post). E, End-systolic image before revascularization (ES pre) demonstrates severe hypokinesis of posterolateral segment (from 2- to 5-o'clock position, one of four apical segments). Mean wall thickening in this segment was 15%. F, End-systolic image during infusion of dobutamine (ES dob) demonstrates modest improvement in same posterolateral segments, but in the normal range (mean wall thickening, 29%). Remaining segments show substantial increase in wall thickening with dobutamine. G, End-systolic image after revascularization (ES post) demonstrates normal wall thickening in posterolateral wall (mean wall thickening, 40%). Remaining segments also show normalization with revascularization.

Image Analysis
Deidentified cine images were analyzed by an investigator (J.M.D., 6 years of cardiac MR imaging experience), blinded to the study time point (before or after revascularization), by using software (Argus; Siemens, Princeton, NJ). Landmarks such as papillary muscles, right ventricular insertion sites, and areas of late gadolinium enhancement were used to match images obtained before and after revasculariztion. Planimetry was performed for endocardial and epicardial areas at end diastole and end systole with exclusion of the papillary muscles from the endocardial area. LV end-diastolic, end-systolic, and stroke volumes; ejection fraction; and mass were measured by using a modified Simpson rule. The percentage of wall thickening both at rest and during administration of dobutamine was measured by using each section (range, 7–11; mean, 9 sections ± 1 per patient) partitioned into six segments at the midventricle and base (average three sections each) and four segments at the apex (average three sections each). Wall thickening was measured as that of the entire segment. Late gadolinium-enhanced regions were defined as those with signal intensity more than 2 standard deviations greater than that of remote normal myocardium. The IT was measured as per a previous study (10) in the same segments as for functional analysis by using planimetry (J.M.D.) and was classified as either no enhancement, 1%–25% IT, 26%–50% IT, or more than 50% IT.

Dysfunctional segments were defined as those that demonstrated wall thickening of less than 27% (2 standard deviations lower than normal in our laboratory, as defined according to a group of 10 healthy human subjects [seven men, mean age, 46 years ± 13] without cardiac history or cardiac risk factors; C.M.K. et al, University of Virginia, unpublished data, 2002). A normal response to dobutamine was considered an improvement in the percentage of wall thickening into the normal range (27%). Improvement in wall thickening was measured as baseline percentage of wall thickening at follow-up minus wall thickening before revascularization.

Statistical Analysis
Volumetric parameters were compared before and after revascularization with a paired t test. Functional parameters according to segment were compared before and after revascularization by using F tests with repeated-measures models. These models used a compound symmetric covariance structure for observations within subjects. Linear regression analysis was used to compare either the percentage of wall thickening with dobutamine or IT with improvement in the percentage of wall thickening after revascularization. Data are presented as an estimated mean ± standard error. A P value of <.05 was considered to indicate a significant difference. Analyses were performed (M.R.C.) by using software (SAS PROC MIXED, release 9.1; SAS Institute Cary, NC).

	RESULTS

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LV Remodeling with Revascularization
LV end-diastolic, end-systolic, and stroke volumes; ejection fraction; and LV mass at rest before and after CABG are depicted in Table 2. No statistically significant changes were noted after CABG.

All 15 patients had segments with 1%–50% IT. Five of the 15 patients also had segments (n = 11) with more than 50% IT. At rest before revascularization, the percentage of wall thickening was inversely related to IT (P < .001, Table 3). The same was true after revascularization (P < .001, Table 3). Sixty percent of segments without enhancement recovered function into the normal range; 40% had 1%–25% IT, 38% had 26%–50% IT, and 9% had more than 50% IT.

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Figure 3: Bar graph shows improvement in the percentage of wall thickening (%WT) from before to after revascularization in all 91 segments with 1%–50% IT according to both IT and dobutamine response (+Dob Res). * = P < .04 versus no dobutamine response (–Dob Res). No difference is seen in improvement in wall thickening between segments with 1%–25% IT and 26%–50% IT, whereas significant difference is noted between dobutamine-responsive and nonresponsive segments.

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Figure 4a: Scatterplots depict results of linear regression analyses. (a) Significant relationship is noted between improvement in percentage of wall thickening after CABG and percentage of wall thickening increase with dobutamine, but not between (b) improvement in percentage of wall thickening after CABG and percentage of IT.

View larger version (11K): [in this window] [in a new window] [Download PPT slide]   Figure 4b: Scatterplots depict results of linear regression analyses. (a) Significant relationship is noted between improvement in percentage of wall thickening after CABG and percentage of wall thickening increase with dobutamine, but not between (b) improvement in percentage of wall thickening after CABG and percentage of IT.

	DISCUSSION

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Viability has been defined in a number of ways. Strictly speaking, viability implies the state of the myocyte, either alive or dead. Late gadolinium-enhanced cardiac MR imaging has been clearly demonstrated to be an accurate marker of the state of the myocyte (8,14). This technique can accurately depict acute and chronic myocardial infarction (15), even if it is small (16). There is a stepwise inverse relationship between IT and the likelihood of functional recovery after reperfusion of acute myocardial infarction (17) or revascularization in chronic ischemic heart disease (10), as assessed qualitatively. Imaging of infarct anatomy performs well at either extreme—no enhancement or greater than 50% IT—where the predictive value for functional recovery, or lack thereof, is good.

In 1%–50% IT, however, the relationship between the anatomy of myocardial infarction and the recovery of function is more complex. Canine studies in nontransmural infarction performed with tagged cardiac MR imaging suggest that recruitable function exists in both subepicardial border zones and within the subendocardium of acute myocardial infarction (18). Low-dose dobutamine-tagged cine cardiac MR imaging has been used in patients with acute myocardial infarction to show that subendocardial response to dobutamine was less predictive of functional recovery than midwall and subepicardial response (19). For this reason, dobutamine response across the entire wall was chosen as the examination of choice in the present study. In addition, the myocardial tags in tagged cine cardiac MR imaging fade during systole when gadolinium is present in the myocardium and are therefore problematic when trying to match to late gadolinium-enhancement images.

The predictive value of 1%–50% IT in chronic ischemic heart disease for functional recovery is between 40% and 60% (10). For this reason, we postulated that dobutamine response might provide additional information to the assessment of the likelihood of functional recovery in these segments. Previous studies have validated dobutamine cine cardiac MR imaging with PET as the standard of reference in patients with chronic myocardial infarction for viability, showing excellent overall accuracy (3). When functional recovery after revascularization was used as a reference standard, dobutamine cine MR imaging performed well, with a sensitivity of 89% and specificity of 94% (6).

Previous animal studies have shown that inotropic reserve in areas of gadolinium enhancement is limited to infarcts with less than 38% IT ± 4 (20). A recent clinical study (11) demonstrated that dobutamine response was superior to late gadolinium enhancement in a similar patient population as in the present study, especially in infarcts with 1%–74% IT. The area under the receiver operating characteristic curve, or AUC, was greater for dobutamine cine cardiac MR imaging (AUC, 0.838) compared with IT (AUC, 0.728) in prediction of recovery. Our study findings are consistent with the aforementioned findings, and we used a quantitative approach in the assessment of both function and IT. Others (21) have demonstrated similar findings in patients with acute myocardial infarction, in whom receiver operating characteristic analysis demonstrated better predictive value for recovery of function for dobutamine cine cardiac MR imaging (AUC, 0.87) compared with IT (AUC, 0.78).

One difference between our study and the study of Kim et al (10) was the size of the segments studied. In the latter study, each short-axis section was divided into 12 segments, whereas a six-segment model in the base and midventricle and a four-segment model at the apex were used in the present study. The latter approach has the effect of reducing the number of segments with more than 50% transmural myocardial infarction, since it takes a very extensive infarction to fit that definition. In addition, the present study used a quantitative measure of wall thickening. This may account in part for the differences in the recovery of wall thickening in segments with 1%–25% and 26%–50% IT between the present study and that of Kim et al (10).

In addition to recovery of rest contractile function, there are many other potential benefits of revascularization (12). Limitation of further infarct expansion and LV remodeling is one potential benefit, in part because of the scaffolding effects of improved blood flow. No adverse remodeling occurred in our group, but there was no control group that was not revascularized. Rest function may not be the ideal end point, as was shown in prior studies (22,23) of revascularization in chronic ischemic heart disease. It was recently demonstrated that contractile reserve several months after revascularization may be a marker of late (3 years after revascularization) recovery of rest function (23). Other potential benefits of revascularization include the limitation of ischemia or further infarction and prevention of arrhythmia. The patients in our study had no intercurrent events in the 20-week follow-up period.

Clinical Implications
Not all patients undergoing pre-revascularization viability testing would need to have low-dose dobutamine infusion. Many patients have segments with little or no late gadolinium enhancement or segments with predominantly transmural enhancement, and the question is moot in those patients. Our data support the concept that there may be an added value in the use of low-dose dobutamine in patients with multiple segments with 1%–50% IT. In addition, low-dose dobutamine may be important when considering revascularization of a single vascular territory with only 1%–50% IT subtended by an occluded or critically stenosed artery. However, as discussed above, there are other potential benefits of revascularization other than the recovery of contractile function.

Addition of a 10-minute infusion of 10 (µg · kg^–1)/min of dobutamine to a cardiac MR imaging study, which includes late gadolinium-enhanced imaging, does increase the complexity of the study but should not be prohibitive. Low-dose dobutamine is generally well tolerated and is not chronotropic and, therefore, does not provoke ischemia, although it requires physician monitoring for safety purposes (monitoring for arrhythmias, etc) and adds 10 minutes to the length of the overall study.

Limitations
Limitations of the present study included the relatively small sample size. Because of the increasing use of multivessel stent placement, especially with the availability of drug-eluting stents, at the same sitting as coronary angiography without preprocedural viability assessment, the number of patients available for such study prior to CABG is declining. Matching of regions imaged before with those imaged after revascularization is always a potential problem, but the tomographic capabilities of cardiac MR imaging along with careful use of landmarks such as papillary muscles, right ventricular insertion sites, and areas of late gadolinium enhancement reduce the impact of this issue. The section thickness for late gadolinium-enhanced cardiac MR imaging and steady-state free precession MR was different and could contribute to segment mismatching due to partial volume effects. In addition, improvement of rest contractile function may be incomplete at the follow-up point (20 weeks after myocardial infarction) chosen for this study (23,24).

In conclusion, recovery of quantified wall thickening after revascularization in chronic ischemic heart disease is inversely proportional to IT. In segments with 1%–50% IT, dobutamine response allows prediction of functional recovery with revascularization.

	ADVANCES IN KNOWLEDGE

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• Dobutamine response allows the prediction of functional recovery with revascularization in segments with 1%–50% infarct transmurality.
  
• Recovery of wall thickening after revascularization is inversely proportional to infarct transmurality.
  

	FOOTNOTES

 

Abbreviations: CABG = coronary artery bypass grafting • IT = infarct transmurality • LV = left ventricular

Authors stated no financial relationship to disclose.

Author contributions: Guarantor of integrity of entire study, C.M.K.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, C.M.B.; clinical studies, C.M.B., J.M.D., S.V., C.M.K.; experimental studies, J.M.D.; statistical analysis, C.M.B., M.R.C.; and manuscript editing, C.M.B., J.M.D., M.R.C.

	References

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This Article Abstract Figures Only Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bove, C. M. Articles by Kramer, C. M. Search for Related Content PubMed PubMed Citation Articles by Bove, C. M. Articles by Kramer, C. M.