Author + information
- Received January 26, 2009
- Revision received February 8, 2010
- Accepted March 5, 2010
- Published online June 1, 2010.
- Sharon W. Kirschbaum, MD⁎†,
- Alexia Rossi, MD†,
- Ron T. van Domburg, PhD⁎,
- Katerina Gruszczynska, MD†,
- Gabriel P. Krestin, MD, PhD†,
- Patrick W. Serruys, MD, PhD⁎,
- Dirk J. Duncker, MD, PhD⁎,
- Pim J. de Feyter, MD, PhD⁎† and
- Robert-Jan M. van Geuns, MD, PhD⁎†⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Robert-Jan van Geuns, Erasmus Medical Center, Thoraxcenter, Room Ba 585, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands
Objectives This study sought to quantify contractile reserve of chronic dysfunctional myocardium, in particular in segments with intermediate transmural extent of infarction (TEI), using low-dose dobutamine cardiac magnetic resonance (CMR) in patients with a chronic total coronary occlusion (CTO).
Background Recovery of dysfunctional segments with intermediate TEI after percutaneous coronary intervention is variable and difficult to predict, and may be related to contractility of the unenhanced rim.
Methods Fifty-one patients (mean age 60 ± 9 years, 76% male) with a CTO underwent CMR at baseline and 35 patients underwent CMR at follow-up to quantify segmental wall thickening (SWT) at rest during 5 and 10 μg/kg/min dobutamine, and at follow-up. Delayed-enhancement CMR was performed to quantify TEI. Dysfunctional segments were stratified according to TEI, end-diastolic wall thickness (EDWT), or unenhanced rim thickness, and SWT was quantified. Segments with an intermediate TEI (25% to 75%) were further stratified according to baseline SWT of the unenhanced rim (SWTUR) (<45% and >45%), and SWT was quantified. For each parameter, odds ratio (OR) and diagnostic performance for the prediction of contractile reserve were calculated.
Results Significant contractile reserve was present in dysfunctional segments with EDWT >6 mm, unenhanced rim thickness >3 mm, or TEI of <25%; only TEI had significant relation with contractile reserve (OR: 0.98; 95% confidence interval [CI]: 0.96 to 0.99; p = 0.02). In segments with intermediate TEI (n = 58), mean SWT did not improve significantly. However, segments with SWTUR <45% showed contractile reserve and improved at follow-up, whereas segments with SWTUR >45% were unchanged. SWTUR had a significant relation with contractile reserve (OR: 0.98; 95% CI: 0.97 to 0.99; p = 0.02).
Conclusions CMR quantification of transmurality of infarcted myocardium allows the assessment of the potential of dysfunctional segments to improve in function during dobutamine of most segments. However, in segments with intermediate TEI, measurement of baseline contractility of the epicardial rim better identifies which segments maintain contractile reserve.
Chronic dysfunctional myocardium can result either from previous myocardial infarction or from hibernating myocardium due to an obstructive atherosclerotic lesion (1). Contrast-enhanced cardiac magnetic resonance (CMR) can identify infarcted myocardium. In patients with chronic dysfunctional myocardium, the likelihood of recovery of segments without infarction is high, whereas segments with complete transmural infarction do not recover after revascularization. However, the likelihood of recovery after revascularization of segments with transmural extent of infarction (TEI) between 25% and 75% is highly variable (2,3). Contractile reserve using low-dose dobutamine can also be used to predict recovery of function after revascularization (4–9) and is described as being a useful addition to delayed-enhancement CMR (10). Surprisingly, the relation between quantitative contractile reserve and TEI in patients with chronic dysfunctional myocardium has not been investigated thus far.
In this study, we quantified contractile reserve in myocardial segments stratified according to 1) the TEI; 2) end-diastolic wall thickness (EDWT); and 3) thickness of the unenhanced rim in patients with chronic dysfunctional myocardium due to a chronic total occlusion (CTO) during low-dose dobutamine, and compared this with SWT at follow-up. We paid particular attention to the evaluation of segments with an intermediate transmural extent of infarction between 25% and 75%. In this group, we investigated the influence of baseline contractility of the epicardial viable rim on contractile reserve and improvement in function after revascularization of the total segment.
Seventy patients with a CTO who were referred for percutaneous coronary intervention (PCI) were prospectively recruited for enrollment in this study. Eight patients (11%) refused to participate. A CTO was classified as a complete occlusion for more than 3 months as obtained from either the clinical history of prolonged anginal chest pain or myocardial infarction or the date of the diagnostic angiogram before revascularization. Exclusion criteria were acute myocardial infarction within the last 3 months; atrial fibrillation; inability to lie flat; and contraindications for magnetic resonance studies. In 11 patients (16%), CMR could not be successfully completed due to claustrophobia (n = 8), obesity (n = 2), and allergic reaction to the contrast agent (n = 1). Ultimately, 51 patients were studied. Of these patients, 78% had a positive exercise test; the remaining 22% had progressive anginal symptoms. Of those 51 patients, 35 patients underwent successful revascularization of their CTO followed by a second CMR scan at 6.2 ± 0.5 months after the procedure. Baseline parameters of all 51 patients are presented in Table 1. The institutional review board of the Erasmus Medical Center approved the study, and all patients gave written informed consent.
CMR images were acquired using a 1.5-T scanner with an 8-element cardiac phased-array receiver coil placed over the thorax (Signa CV/i, GE Medical systems, Milwaukee, Wisconsin). Cine CMR was performed using a steady-state free-precession technique (FIESTA). Imaging parameters were: field of view 36 to 40 × 28 to 32 cm; matrix size was 224 × 196; repetition time, 3.4 ms; echo time, 1.5 ms; flip angle, 45°; 12 views per segment; and slice thickness was 8.0 mm with a 2.0-mm slice gap. The 2- and 4-chamber end-diastolic images at end-expiration provided the reference images to obtain 10 to 12 cine breath-hold short-axis images to cover the entire left ventricle.
Dobutamine was infused at 5 and 10 μg/kg/min for 5 min at each dosage using an intravenous catheter, which was placed in the antecubital vein. Functional imaging was repeated using the same long-axis imaging planes as at rest. For the short axis, we used 3 slices: basal, mid-ventricular, and apical. During the test, the patients were monitored using continuous ECG leads, and blood pressure was measured every 3 min.
Delayed-enhancement imaging was performed with a gated breath-hold T1-weighted inversion-recovery gradient echo sequence 20 min after infusion of gadolinium-diethyltriamine pentaacetic acid (0.2 mmol/kg intravenously, Magnevist, Schering, Germany). Imaging parameters were repetition time 6.3, echo time 1.5, flip angle 20°, inversion pulse of 180°, matrix 192 × 160, number of averages 1 to 2, and inversion time 180 to 280 ms (adjusted to null the signal of the remote myocardium). The slice locations of the delayed-enhanced images were copied from the cine images.
Definitions and data analysis
The images were analyzed using the CAAS-MRV program (version 3.1; Pie Medical Imaging, Maastricht, the Netherlands). Papillary muscles and trabeculations were considered as being part of the blood pool volume. A 16-segment-model, excluding the apex, was used to analyze the myocardial wall in each patient (11). Segmental wall thickening of the full wall (SWTFW) was assessed quantitatively at rest, during 5 and 10 μg/kg/min dobutamine, and at follow-up, and was considered dysfunctional if wall thickening was less than 45% (12). Contractile reserve was present if SWTFW increased >10% after administration of either 5 or 10 μg/kg/min dobutamine. SWTFW was analyzed in dysfunctional segments in the perfusion territory of a CTO before and 6.2 ± 0.5 months after revascularization. Segments were stratified according to TEI, EDWT, and the thickness of the unenhanced rim, and SWTFW was determined according to these parameters for each segment. The diagnostic angiogram was visually scored by 2 experienced observers. The place of occlusion and left or right dominance was established, and the left ventricular segments were correlated to vessel anatomy. The TEI was analyzed quantitatively by dividing the hyper-enhanced area using computer-assisted tracings by the total area in each segment and expressed as a percentage. TEI was divided into 4 groups; <25%, 25% to 50%, 50% to 75%, and >75% infarct transmurality per segment. EDWT was divided into 3 groups; <6 mm (6), 6 to 8 mm, and >8 mm. The thickness of the unenhanced rim (Fig. 1) was defined as the mean wall thickness of the nonenhanced area of a segment and was also divided into 3 groups; <3 mm (13), 3 to 6 mm, and >6 mm. Segmental wall thickening of only the unenhanced rim (SWTUR) was measured quantitatively in segments with an intermediate TEI (between 25% and 75%) and divided into 2 groups: dysfunctional (SWTUR: <45%) and normokinetic (SWTUR: >45%). For SWTUR, the increase in wall thickness in the end-systolic phase as compared to the end-diastolic phase was assigned to the thickness of the unenhanced rim, because we assume that scar tissue does not contract, and is expressed as a percentage of the unenhanced rim (Fig. 2).
Data are presented as mean ± standard deviation. Dysfunctional segments were either stratified into the TEI, or the EDWT or the thickness of the unenhanced rim. To investigate the differences of SWT during rest, dobutamine and follow-up for TEI, EDWT, and the unenhanced rim, variance analysis with repeated measurements was used. Post-hoc analysis was performed using the Tukey Student range method. The change in hemodynamic parameters during infusion of dobutamine, and the contractile reserve in dysfunctional segments with an intermediate extent of infarction, were also tested using analysis of variance followed by the Tukey Student range method. To investigate whether these parameters were related with dobutamine, multivariable logistic regression analyses were used. All analyses were adjusted for demographics (age, gender, body mass index), clinical factors (hypertension, diabetes, hypercholesterolemia, smoking, family history of cardiac disease), and medications (beta-blocker, aspirin, ACE-inhibitor, and statin). The goodness of fit of the model was calculated by the chi-square test. Interaction terms were included in the models to investigate confounding between these parameters. The area under the receiver operator curve (AUROC) was calculated and the diagnostic performance for EDWT (cutoff: 6 mm ), TEI (cutoff: 50% ), unenhanced rim thickness (cutoff: 3 mm ) and SWTUR (cutoff: 45%) to predict the presence of contractile reserve were calculated. All data analysis was performed with SPSS for Windows 15.0.0 (SPSS Inc., Chicago, Illinois).
In 22 (43%) patients, the CTO was located in the left anterior descendent coronary artery, in 9 (18%) patients in the left circumflex coronary artery, and in 20 (39%) patients in the right coronary artery. Of the 51 patients that were included in the study, 45 (88%) patients had an infarct of which 43 (84%) were in the perfusion territory of the CTO. All images were of sufficient quality for analysis. Administration of dobutamine was well tolerated by all patients; no serious side effects occurred. All hemodynamic parameters that were measured increased slightly but consistently during infusion of dobutamine (Table 2). Of those 51 patients, 35 patients underwent successful revascularization of their CTO, 16 (46%) of the left anterior descendent coronary artery, in 7 (20%) patients in the left circumflex coronary artery, and in 12 (34%) patients in the right coronary artery; these patients underwent a follow-up CMR scan. In 1 patient, new hyperenhancement occurred in the anteroseptal wall. The new infarct mass was 9 g.
Two hundred seventy-nine segments were in the perfusion territory of the CTO. Mean SWT of all CTO perfused segments (normokinetic + dysfunctional segments) was 36 ± 34% at baseline and increased to 43 ± 41% during 5 μg/kg/min and 44 ± 42% during 10 μg/kg/min of dobutamine (both p < 0.001 vs. baseline). SWT of remote segments amounted to 78 ± 27% at baseline, 71 ± 42% during 5 μg/kg/min, and 82 ± 41% during 10 μg/kg/min (p = 0.20).
Of the CTO perfused segments, 163 segments (60%) were dysfunctional (Fig. 3). During low-dose dobutamine stress, 92 (56%) of the dysfunctional segments at baseline conditions manifested a difference in contractile reserve of more than 10% after 10 μg/kg/min dobutamine. Mean SWT of all dysfunctional CTO perfused segments increased from 16 ± 19% at baseline to 30 ± 34% during 5 μg/kg/min dobutamine and to 31 ± 34% during 10 μg/kg/min dobutamine (both p < 0.0001 vs. baseline).
Contractile Reserve in Dysfunctional Segments and SWT at Follow-up
Segments were stratified using 3 parameters: TEI, the EDWT, or the thickness of the unenhanced rim. For each of these parameters, SWT at rest and during infusion of dobutamine was calculated according to the group definition and presented in Table 3. Mean SWT increased significantly during 5 μg/kg/min dobutamine in segments with an EDWT >6 mm, unenhanced rim of >3 mm, or if TEI <25%. For segments with TEI between 25% and 50%, SWT only improved during a higher dose of 10 μg/kg/min dobutamine. SWT during dobutamine infusion remained significantly lower for all segments in the area distal to the CTO as compared with segments in the remote area. The frequency of segments with contractile reserve is presented in Table 4.
Interaction terms between EDWT, TEI, and unenhanced rim turned to be far from significant. Multivariate logistic regression analysis including baseline characteristics showed that TEI was the only parameter that could predict contractile reserve (odds ratio [OR]: 0.98; 95% confidence interval [CI]: 0.96 to 0.99; p = 0.02 and AUROC of 0.66; 95% CI: 0.57 to 0.75; p = 0.001). Unenhanced rim thickness and EDWT could not predict contractile reserve (AUROC: 0.63; 95% CI: 0.54 to 0.72; p = 0.009 and AUROC: 0.52; 95% CI: 0.42 to 0.61; p = 0.74, respectively) (Table 5). Adding TEI to the multivariate model including demographic and clinical factors and medication improved the chi-square value of the model significantly (from 29 to 34, p < 0.01). Sensitivity, specificity, positive predictive value, and negative predictive value were given in Table 5.
In the subgroup of 35 patients that underwent PCI, SWT was calculated before and after PCI according to the same group definition as described earlier and presented in Figure 4. SWT before PCI was significantly different as compared with SWT at follow-up. Importantly, SWT during dobutamine before revascularization was not statistically different as compared with SWT at follow-up.
Segments With Intermediate TEI
In 35 patients that underwent PCI, 58 segments had a TEI between 25% and 75%. Contractile reserve was present in 71% (41/58) of the segments and 61% (36/58) of the segments improved after revascularization. Of the segments that show contractile reserve (n = 41), 34 improved after revascularization (83%). This is in contrast to segments without contractile reserve (17/58) where only some of the segments improved at follow-up (2/17; 12%).
To discriminate which of the segments with an intermediate TEI will show contractile reserve and will improve after revascularization, we used another parameter, SWTUR. In segments with SWTUR of >45% (n = 13), mean SWTFW at rest did not change significantly during 5 μg/kg/min dobutamine (p = 0.66), 10 μg/kg/min dobutamine (p = 0.22), and at follow-up (p = 0.44). Seven of the 13 segments (54%) did not show contractile reserve, and 69% (9/13) of the segments did not improve after PCI.
In segments with SWTUR <45% (n = 45), mean SWTFW at rest increased significantly during 5 μg/kg/min (p < 0.05), 10 μg/kg/min (p < 0.01), and at follow-up (p < 0.0001) (Fig. 5). In contrast to segments with an intermediate TEI and SWTUR >45%, intermediate segments with an SWTUR <45% frequently show contractile reserve (34/45; 74%) and improvement after PCI (31/45; 67%).
Multivariate logistic regression analysis for each viability parameter, including baseline characteristics, was performed to investigate the importance of all viability parameters. This demonstrated the importance of SWTUR, as it was the only parameter in the segments with an intermediate TEI with a significant relation with the outcome parameter (OR: 0.98; 95% CI: 0.97 to 0.99; p = 0.02 and AUROC of 0.70; 95% CI: 0.58 to 0.82; p = 0.003) (Table 6). Addition of SWTUR to the model improved the chi-square value of the model significantly (from 9 to 14, p < 0.01). Sensitivity, specificity, positive predictive value, and negative predictive value of SWTUR for the prediction of contractile reserve were as follows: 79% (63 to 89), 52% (33 to 79), 69% (54 to 81), and 64% (42 to 81).
In our study, we demonstrated that dysfunctional myocardial segments in the territory of a CTO improved significantly during dobutamine and at follow-up if EDWT was >6 mm, TEI <25%, or if the thickness of the epicardial unenhanced rim was >3 mm. However, only TEI could predict contractile reserve. This study furthermore showed that the functionality of the epicardial viable rim allows refined assessment of contractile reserve and the change in SWT at follow-up for segments with a TEI between 25% and 75%.
Low-dose dobutamine improves cellular energetics and contractile function in hypoperfused myocardium (14). Subsequently, the test simulates the effect of revascularization with a high accuracy (15–17), whereas TEI is less accurate for prediction of improvement in function, especially in segments with an intermediate extent of infarction (10). Kim et al. (2) reported that the likelihood of recovery was inversely related to TEI, yet the likelihood of recovery following revascularization was less predictable in segments with a TEI between 25% and 75%, and only 25% of the segments recovered after revascularization in this subgroup (2). The number of dysfunctional segments with a TEI of 25% and 75% is substantial, and additional parameters seem necessary for accurate prediction of improvement. The TEI is a relative value that omits the thickness of a segment. The amount of contractile reserve will probably be less in segments with an EDWT of 3 mm with 50% TEI as compared with a segment with the same infarct transmurality and an EDWT of 8 mm. It is may be therefore interesting to measure the thickness of the epicardial viable unenhanced rim. Second, the amount of rest function of the epicardial unenhanced rim is important for its contribution to regional wall thickening after revascularization. The relative contribution to SWTFW of restoring function of an akinetic epicardial unenhanced area is more than restoring function of a normal contracting epicardial unenhanced area.
These more complex analyses can easily be assessed by current post-processing techniques allow quantification of the CMR images, which provide more refined and accurate assessment of the extent of scar tissue, the extent and functionality of the viable epicardial tissue, and the presence of contractile reserve of dysfunctional myocardial segments.
We confirmed findings of other studies that showed that the presence of a small unenhanced rim was associated with a higher probability of nonviable tissue as assessed by positron emission tomography studies (13,18). In our study, the presence of an unenhanced rim thickness of <3 mm is associated with absence of contractile reserve and absence of change in SWT after PCI.
Furthermore, this study shows that if SWTUR is more than 45% in the case of intermediate TEI, no contractile reserve and no change in SWT after PCI were present. On the other hand, if systolic wall thickening was less than 45% in these segments, contractile reserve could be elicited by low-dose dobutamine, and SWT changed significantly at follow-up. This concept has been further explained and illustrated (Fig. 2). Theoretically, if 50% of a dysfunctional segment (SWTFW <45%) in the perfusion territory of a CTO is marked by the contrast agent, and therefore considered as scar tissue, and the remaining 50% of that segments is viable, but akinetic or hypokinetic, contractility will increase during dobutamine infusion, and SWT will change after PCI. If the remaining nonenhanced part in a segment with the same TEI of 50% is not dysfunctional (SWTUR >45%), total wall thickening will still be classified as dysfunctional (below 45%) although no contractile reserve and no change in SWT after PCI will be present. This theoretical model assumes that scar tissue does not contract and that therefore the SWT of the segments should be ascribed to the contractility of the unenhanced rim both at baseline and during low-dose dobutamine infusion. Our study provides evidence for the additional value of quantitative determination of rest function of the unenhanced rim to assess the presence of viable tissue.
Due to the limited number of patients, we could only perform segmental analysis in this report where interaction between individual segments of a patient can be present.
CMR quantification of infarcted myocardium provides precise delineation of the TEI and the unenhanced rim, and allows assessing the potential of dysfunctional segments to show contractile reserve. However, TEI fails to predict contractile reserve in the intermediate segments; in these segments, wall thickening of the unenhanced rim at rest can be used to determine the presence of contractile reserve of the total segment.
- Abbreviations and Acronyms
- area under the receiver operator curve
- cardiac magnetic resonance
- chronic total coronary occlusion
- end-diastolic wall thickness
- percutaneous coronary intervention
- segmental wall thickening full wall
- segmental wall thickening unenhanced rim
- transmural extent of infarction
- Received January 26, 2009.
- Revision received February 8, 2010.
- Accepted March 5, 2010.
- American College of Cardiology Foundation
- Rahimtoola S.H.
- Arnese M.,
- Cornel J.H.,
- Salustri A.,
- et al.
- Baer F.M.,
- Theissen P.,
- Schneider C.A.,
- et al.
- Trent R.J.,
- Waiter G.D.,
- Hillis G.S.,
- McKiddie F.I.,
- Redpath T.W.,
- Walton S.
- Wellnhofer E.,
- Olariu A.,
- Klein C.,
- et al.
- Cerqueira M.D.,
- Weissman N.J.,
- Dilsizian V.,
- et al.
- Holman E.R.,
- Buller V.G.,
- de Roos A.,
- et al.
- Kuhl H.P.,
- van der Weerdt A.,
- Beek A.,
- Visser F.,
- Hanrath P.,
- van Rossum A.
- Yi K.D.,
- Downey H.F.,
- Bian X.,
- Fu M.,
- Mallet R.T.
- Nelson C.,
- McCrohon J.,
- Khafagi F.,
- Rose S.,
- Leano R.,
- Marwick T.H.
- Baer F.M.,
- Theissen P.,
- Crnac J.,
- et al.
- Knuesel P.R.,
- Nanz D.,
- Wyss C.,
- et al.