Incremental Value of Strain Rate Analysis as an Adjunct to Wall-Motion
http://www.100md.com
《循环学杂志》
the University of Queensland Department of Medicine (L.H., C.J., L.J., C.C., C.H., T.H.M.) and the Department of Cardiothoracic Surgery (J.M.), Princess Alexandra Hospital, Brisbane, Australia.
Abstract
Background— Assessment of myocardial viability based on wall-motion scoring (WMS) during dobutamine echocardiography (DbE) is difficult and subjective. Strain-rate imaging (SRI) is quantitative, but its incremental value over WMS for prediction of functional recovery after revascularization is unclear.
Methods and Results— DbE and SRI were performed in 55 stable patients (mean age, 64±10 years; mean ejection fraction, 36±8%) with previous myocardial infarction. Viability was predicted by WMS if function augmented during low-dose DbE. SR, end-systolic strain (ESS), postsystolic strain (PSS), and timing parameters were analyzed at rest and with low-dose DbE in abnormal segments. Regional and global functional recovery was defined by side-by-side comparison of echocardiographic images before and 9 months after revascularization. Of 369 segments with abnormal resting function, 146 showed regional recovery. Compared with segments showing functional recovery, those that failed to recover had lower low-dose DbE SR, SR increment (SR), ESS, and ESS increment (ESS) (each P<0.005). After optimal cutoffs for the strain parameters were defined, the sensitivity of low-dose DbE SR (78%, P=0.3), SR (80%, P=0.1), ESS (75%, P=0.6), and ESS (74%, P=0.8) was better though not significantly different from WMS (73%). The specificity of WMS (77%) was similar to the SRI parameters. Combination of WMS and SRI parameters augmented the sensitivity for prediction of functional recovery above WMS alone (82% versus 73%, P=0.015; area under the curve=0.88 versus 0.73, P<0.001), although specificities were comparable (80% versus 77%, P=0.2).
Conclusions— The measurement of low-dose DbE SR and SR is feasible, and their combination with WMS assessment improves the sensitivity of viability assessment with DbE.
Key Words: heart failure echocardiography imaging myocardial infarction stress
Introduction
Evidence of residual viable tissue within the infarct zone has been reported in &50% of segments after myocardial infarction (MI),1 implying a potential for recovery2–5 and prognostic benefit after revascularization.6–9 Prediction of functional recovery, based on detection of contractile reserve with dobutamine echocardiography (DbE), is of comparable accuracy to alternative techniques, including myocardial perfusion imaging, metabolic imaging with conventional scintigraphy, and positron emission tomography.10 However, although DbE is a widely available and low-cost approach for the detection of viable myocardium, its assessment remains subjective and relies on semiquantitative evaluation of endocardial excursion and wall thickening, which requires adequate training of the observer.11
Editorial p 3820
Strain-rate imaging (SRI) is based on the determination of gradients of myocardial velocity between 2 points in space.12 SR and its integral, strain, have been validated as methods to quantify regional myocardial function.13,14 Although a number of animal studies have examined the relation of both resting SRI and its Db response with evidence of viability after MI,15–17 only one human study has validated the technique as a clinical tool, and that study correlated the Db response with metabolic evidence of viability by positron emission tomography.18 Therefore, we sought to assess the feasibility and accuracy of SRI and strain during DbE for the prediction of functional recovery in patients undergoing revascularization after MI, its incremental value to conventional wall-motion scoring (WMS), and the optimal SRI parameter for this purpose.
Methods
Study Design
We performed SRI in all patients presenting to the echocardiography laboratory for DbE assessment of myocardial viability in the context of left ventricular (LV) dysfunction due to previous MI (>6 weeks before). Fifty-five consecutive patients (mean age, 64±10 years; 9 women; mean ejection fraction [EF], 36±8%) who subsequently underwent revascularization by percutaneous coronary intervention or coronary artery bypass grafting were entered into the study. Functional recovery was assessed on a follow-up 2D echocardiogram performed 9 months after revascularization (Figure 1).
Db Stress Echocardiography
Images were obtained with a standard commercial echocardiography system (Vivid Five or Seven, GE Vingmed) and were stored digitally and on tape for subsequent analysis. Parasternal long-axis and short-axis views, as well as 3 standard apical views (4 chamber, 2 chamber, and long axis) were acquired at rest and at each stage during the Db stress study. The LV was divided according to the 16-segment model of the American Society of Echocardiography. A standard Db-atropine stress protocol was performed, starting at a Db infusion rate of 5 μg · kg–1 · min–1 and increasing every 3 minutes to 10, 20, 30, and 40 μg · kg–1 · min–1.19 When 85% of age-predicted maximal heart rate was not achieved and the test result was negative, atropine was given in 0.25-mg increments up to a maximum of 1.2 mg until the target heart rate was achieved. Blood pressure and a 12-lead ECG were recorded at baseline and at the end of every stage.
Two independent observers, blinded to the patients’ clinical data, used both side-by-side digital displays and videotape to score each LV segment at rest and during Db stimulation as 1=normokinetic, 1.5=mildly hypokinetic, 2=moderate to severely hypokinetic, 3=akinetic, or 4=dyskinetic. A segment was considered viable if it improved by at least 1 grade with low-dose Db infusion (5 to 10 μg · kg–1 · min–1). The viable response could either be uniphasic (sustained improvement at peak Db dose) or biphasic (subsequent worsening of WMS at peak Db dose). Patients were considered to have global myocardial viability if 4 or more segments demonstrated improvement (uniphasic or biphasic response) during DbE, based on previous studies demonstrating that this is associated with a significant improvement in LVEF after revascularization.20
Strain Rate Imaging
SRI was performed from the apical long-axis and 2- and 4-chamber views during gray-scale image acquisition at rest and after each stage of DbE. This technique uses color tissue Doppler velocity measurements in each pixel of a sample line to determine spatial velocity gradients along the ultrasound beam according to the equation SR=[v(r)–v(r+r)]/r, as described previously.13 Distance along the ultrasound beam is denoted r and tissue velocity is denoted v. To ensure optimization of signal quality and reduction in signal noise, especially at peak stress, SRI was performed with harmonic imaging and high spatial resolution (24 beams, frame rates varying between 100 and 187 frames per second).21 Images were obtained at each stage, taking care to align the ventricular walls with the ultrasound beam and to obtain the image during breath-hold if possible. At least 3 cardiac cycles were captured and stored digitally.
SR and Strain Measurements
Analysis was performed offline with dedicated software (EchoPAC-PC, GE Vingmed). Measurements were made in each segment of the same model used for WMS, avoiding walls that were poorly visualized, and with insonation angles >30°.22 The region of interest (12x6 mm) was tracked manually in the 2D image on a frame-to-frame basis and maintained in a fixed midmyocardial position to make sure that SR traces represented the same myocardial segment for the whole cardiac cycle.
Tissue velocity measurements were measured at rest and with low-dose Db in 146 segments (in the first 27 patients enrolled into the study), including isovolumic contraction, peak systolic velocity, and time-to-peak (TTP) systolic velocity. The SR and strain measurements used in this study are summarized in Figure 2 and were measured in 369 segments with abnormal resting WM during DbE (55 patients). Peak longitudinal systolic SR was determined as the maximal negative SR within 350 ms after the QRS complex, and isovolumic contraction preceding SR was also documented. Three timing parameters were measured, namely, (1) TTP systolic SR, measured as the difference in time from the end of diastole (corresponding to mitral valve closure, as extracted from the velocity curve and the curved anatomic M mode) to peak SR; (2) time to onset of shortening according to the SR curve, measured as the difference in time from the end of diastole to the onset of negative deflection of the SR curve; and (3) time to end of shortening according to the SR curve, measured as the difference in time from the end of diastole to the zero crossover of the SR curve at the end of systole. End-systolic strain (ESS; the time integral of SR) was measured as the magnitude of strain at aortic valve closure (timed from the velocity curve and curved anatomic M mode). When further shortening occurred after aortic valve closure (end of systole), this was measured as the peak strain (PkS). The difference between ESS and PkS was calculated as the postsystolic shortening (PSS), and from this, the postsystolic index (PSI), expressed as a percentage, was derived from the equation (PSS/PkS)x100.23
Revascularization and Follow-Up
All patients underwent coronary angiography and subsequent revascularization after DbE. The choice of percutaneous or surgical revascularization was based on clinical judgment by the treating physician. Follow-up echocardiography was performed 9 months after revascularization. Segments with resting dysfunction that were adequately revascularized we deemed viable if regional function had improved on side-by-side comparison by observers blinded to the clinical and DbE data. EF was calculated by Simpson’s biplane method for each follow-up study; global functional recovery was identified if the EF had improved by 5% on 2D echocardiography. None of the patients had recurrent angina or clinical events between revascularization and follow-up.
Statistics
Data are expressed as the mean±SD. SPSS for Windows (release 11.0, SPSS Inc) was used for basic statistical analyses, with Stata (version 8, Stata Corp) being used for repeated-measures analyses. Comparisons between segments showing functional recovery at follow-up and those that did not were performed with t tests for continuous variables and 2 tests for categorical variables. The ability of velocity and SRI parameters to predict functional recovery was explored with a random-effects model to address the issue of repeated observations (data on multiple segments per patient used in the analysis). The output from this analysis allowed the derivation of receiver operating characteristic (ROC) curves, which were used to designate cutoffs. However, independent predictors were the same in multivariate models produced by either method, and odds ratios (ORs) for prediction of functional recovery were similar. Multivariate models were performed by forward selection of variables with the likelihood-ratio test for inclusion until the most parsimonious model was found. First-order interaction terms were tested. Goodness of fit was explored with the Hosmer-Lemeshow test, and regression diagnostics were checked. Probability values of P<0.05 were considered statistically significant. The area under the curve (AUC) and ROC curve was calculated for each parameter, and curves were examined to define optimal cutoffs for the prediction of functional recovery. Using these cutpoints, we compared the sensitivity and specificity of WMS with that of SR and ESS parameters for prediction of functional recovery according to the McNemar test.24
Results
Study Group
Table 1 summarizes the clinical characteristics, cardiac risk factors, and current antianginal therapy in the 21 patients who showed global functional recovery (EF baseline versus follow-up, 34±9% versus 47±10%) and the 34 patients who did not (38±8% versus 38±7%). No differences were identified between the groups, who also showed comparable responses to Db stress (Table 2).
Db Stress Echocardiography
A total of 880 segments were evaluated on DbE, of which 369 segments had abnormal resting WM (hypokinetic, akinetic, or dyskinetic). A uniphasic response was identified on WMS in 50 segments (14%), and a biphasic response was present in 107 (29%); 212 segments (57%) showed no augmentation with Db. Of the 369 abnormal segments, we were able to acquire WMS and SRI measurements for 350. Of the 146 (42%) showing functional recovery on follow-up echocardiography, 106 were predicted by WMS (sensitivity, 73%; 95% confidence interval [CI], 68% to 78%). There was no functional recovery in 204 segments (58%), among which WMS predicted failure to recover in 156 (specificity, 77%; 95% CI, 73% to 81%).
Feasibility of SRI and Interobserver Variability
We were able to perform SR and strain analysis in 350 (95%) of the segments with abnormal resting WM. Failure to perform measurements was related to poor visualization of the segment or an insonation angle >30° in 9 segments at rest and in 10 with low-dose Db.
SR and strain analyses were also performed by an independent observer in a total of 40 abnormal segments (5 patients). Table 3 summarizes the interobserver variability for SR, ESS, and timing parameters at rest and with low-dose Db. We evaluated the components of variance with a general linear model and showed that neither patient nor observer factors accounted for a significant proportion of interobserver variability.24 The intraobserver variability for rest and follow-up EF was 2±4%, with similar values for interobserver variability.
Tissue Velocity Measurements
Table 4 summarizes the results of the ability of resting and low-dose DbE tissue velocity measurements in segments to predict functional recovery. None of the tissue velocity measurements were predictive of functional recovery.
Prediction of Functional Recovery With SRI
The resting SRI parameters in segments with and without functional recovery are summarized in Table 5. The only resting SRI parameter predictive of functional recovery was ESS (AUC=0.60). However, resting ESS was not a significant predictor of functional recovery in any of the combined WMS and SRI parameter models, as determined by logistic-regression analysis (see following section).
Table 6 and Figure 3 summarize the low-dose DbE SRI measurements in segments that did and did not recover and that were predictive of functional recovery. The greatest AUCs for the ROC curves were obtained for low-dose Db SR (AUC=0.84, SE=0.02), SR increment (SR) from rest to low-dose Db (AUC=0.82, SE=0.02), low-dose Db ESS (AUC=0.84, SE=0.02), and ESS increment (ESS) from rest to low-dose Db (AUC=0.84, SE=0.03). All of these AUCs significantly exceeded results for WMS (AUC=0.73, SE=0.027; all P<0.001). The AUC for low-dose Db SR was also significantly greater than for SR (P=0.02) and for ESS from rest to low-dose Db (P<0.001). PSI at low-dose Db was significantly lower in segments that recovered compared with those that did not, and the change in PSI from rest to low-dose Db was significantly larger in segments that showed functional recovery. Timing parameters were also different between segments that showed functional recovery and those that did not (Table 6), but the diagnostic content was less, as evidenced by smaller AUCs for the ROC curves.
All low-dose Db SRI measures were predictive of functional recovery in the univariate model, but only low-dose Db SR (OR, 0.16; 95% CI, 0.046 to 0.57; P=0.004) and SR (OR, 0.19; 95% CI, 0.068 to 0.54; P=0.002) were independently predictive in the multivariate model. Table 6 includes the adjusted OR for the prediction of functional recovery by WMS. The unadjusted OR was 8.19 (95% CI, 3.91 to 17.18; P=0.0001).
Comparison of Echocardiographic Techniques for Prediction of Functional Recovery
By applying the optimal cutoff points for SRI parameters from the ROC curves, we compared the sensitivity and specificity of WMS and SRI parameters for the prediction of segmental functional recovery (Figure 4). Compared with WMS (sensitivity, 73%; specificity, 77%), magnitude parameters with low-dose Db were more sensitive but had similar specificity for the prediction of segmental functional recovery. Figure 5 illustrates the improvement in SR and ESS with low-dose Db in a segment that improved (and showed improvement of resting SR and ESS) at follow-up.
Incremental Value of SRI for Prediction of Segmental Functional Recovery
Logistic-regression analysis was used to create a model for prediction of segmental functional recovery based on a combination of WMS and SRI parameters. By using low-dose Db SR and SR increments as continuous variables and WMS as a categorical variable (viable segment=1, nonviable segment=0), we derived a composite score for prediction of recovery: viability score=(1.7xWMS)–(1.8xlow-dose Db SR)–(1.7xSR increment).
By applying a score cutoff of >2.55 (Figures 3 and 4), the model predicted segmental functional recovery with a sensitivity and specificity of 82% (P<0.015) and 80% (P=0.2), respectively, compared with WMS. The AUC for the ROC curve for the viability model (0.882) was significantly greater compared with all other individual SRI parameters and WMS (P<0.001).
Incremental Value of SRI for Prediction of Global Functional Recovery
There were 4 abnormal segments per patient in 47 patients, which allowed us to determine the incremental value of SRI for the prediction of global functional recovery. The presence of 4 segments with enhancement of function by WMS with low-dose Db predicted 15 of the 21 patients who showed global functional recovery, defined by an EF improvement >5% (sensitivity, 71%; 95% CI, 58% to 84%), and predicted failure to recover in 22 of the 26 patients who did not show functional recovery (specificity, 85%; 95% CI, 75% to 95%). The viability model (viability score >2.55 in 4 segments) was similar in sensitivity and specificity in the prediction of global recovery (sensitivity, 67%; 95% CI, 54% to 80%; specificity, 89%; 95% CI, 80% to 97%).
Discussion
The results of this study show that SRI provides a feasible and quantitative technique that is at least comparable in specificity but more sensitive than visual assessment of WMS in the prediction of regional/segmental functional recovery. There is little to choose between the SRI parameters for detection of regional viability, but low-dose Db SR and ESS are the simplest and are less likely to be influenced by noise in the waveforms than is the difference between parameters. A viability model that integrated SRI parameters and WMS gave the best sensitivity and specificity for the prediction of functional recovery, with incremental improvement in sensitivity compared with WMS alone.
DbE Identification of Myocardial Viability
DbE has been widely used for assessment of myocardial viability.10 However, the interpretation of stress echocardiograms is highly subjective and requires special training,25 and even after this, low interinstitutional observer agreement has been described26 and has persisted, despite technical developments.11 A modality allowing objective quantitative analysis of WM and WM response to stress, which can be incorporated into clinical practice, is needed to improve the reproducibility of stress echocardiography. To date, quantitative techniques have been shown to facilitate the identification of abnormal studies,27,28 but little work has been done to facilitate the particularly difficult stress echocardiography application of viability assessment.
SRI and Myocardial Viability
Tissue Doppler imaging has been applied to the detection of myocardial viability with limited success.28 This experience reflects the lack of site specificity of tissue Doppler, in which the velocity of a segment relative to the transducer may be influenced by the behavior of adjacent segments. As expected, none of the tissue velocity measurements in our study were predictive of functional recovery.
SR overcomes these limitations, being little influenced by overall heart motion, cardiac rotation, and motion induced by tethering to adjacent abnormal segments, which can also influence the accuracy of DbE.29,30 Consequently, SRI has been considered to be a more accurate marker than tissue Doppler for the detection of regional myocardial function and has been applied in various animal31–33 and human34–37 studies for the detection of myocardial ischemia and MI.
The ability of SRI to quantify changes in normal myocardial function at varying inotropic states and heart rates was studied in an animal model by Weidemann et al.15,16 From that study, it was concluded that both SR and ESS could quantify changes in myocardial function during clinical stress echocardiography. SR reflected regional contractile function, being uncorrelated with heart rate, whereas ESS was more reflective of EF. In a different animal model, Weidemann et al17 also used SRI to study the regional deformation characteristics of both chronic nontransmural and transmural infarctions before and after Db challenge. Transmural scar extent was correlated closely with ESS at baseline. Nontransmural infarcted myocardium had significantly lower SR and ESS values at baseline, and SR increased with low-dose Db infusion, whereas ESS showed no change. For transmural infarctions, both deformation parameters showed no change during incremental Db infusion.
The only reported clinical application of SRI for the assessment of myocardial viability in patients with depressed LV function after MI was reported by Hoffmann et al.18 That study showed that an increase of peak systolic myocardial SR during low-dose Db stimulation was correlated with evidence of residual metabolic activity, based on the uptake of [18F]deoxyglucose, and could accurately discriminate between different myocardial viability states. However, ESS, postsystolic shortening, and timing parameters were not studied.
Our work builds on that study by comparing the accuracy of various SRI parameters for prediction of functional improvement after revascularization. We identified low-dose Db SR and SR as the most sensitive and specific markers of viability, which is in keeping with previous studies. In addition to this, low-dose Db ESS and ESS were predictive of functional recovery, whereas the timing parameters, PSS, and PSI were less accurate. By integrating these SRI parameters and WMS into a viability model, we were able to increase the sensitivity of the technique for prediction of functional recovery.
Study Limitations
Despite improvements, SRI (more so than its integral, strain) is still limited by signal noise, and both remain angle dependent.22 We tried to minimize these problems by acquiring tissue velocity data with adequate temporal and spatial resolution, as well as taking care that the ventricular walls were aligned with the ultrasound beam within 30° during image acquisition. Finally, we did not attempt to quantify deformation in the different myocardial layers because of concern that lateral resolution was insufficient to acquire this at 16-cm depth in the adult heart. These data therefore reflect average longitudinal deformation across the entire wall and cannot assess the role of the different myocardial layers in the prediction of functional recovery.
Conclusions
The combination of SRI with low-dose DbE is clinically feasible for the detection of myocardial viability and adds incremental value to expert WMS.
Acknowledgments
This study was supported by a project grant (210218) from the National Health and Medical Research Council, Canberra, Australia.
Disclosures
None.
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Abstract
Background— Assessment of myocardial viability based on wall-motion scoring (WMS) during dobutamine echocardiography (DbE) is difficult and subjective. Strain-rate imaging (SRI) is quantitative, but its incremental value over WMS for prediction of functional recovery after revascularization is unclear.
Methods and Results— DbE and SRI were performed in 55 stable patients (mean age, 64±10 years; mean ejection fraction, 36±8%) with previous myocardial infarction. Viability was predicted by WMS if function augmented during low-dose DbE. SR, end-systolic strain (ESS), postsystolic strain (PSS), and timing parameters were analyzed at rest and with low-dose DbE in abnormal segments. Regional and global functional recovery was defined by side-by-side comparison of echocardiographic images before and 9 months after revascularization. Of 369 segments with abnormal resting function, 146 showed regional recovery. Compared with segments showing functional recovery, those that failed to recover had lower low-dose DbE SR, SR increment (SR), ESS, and ESS increment (ESS) (each P<0.005). After optimal cutoffs for the strain parameters were defined, the sensitivity of low-dose DbE SR (78%, P=0.3), SR (80%, P=0.1), ESS (75%, P=0.6), and ESS (74%, P=0.8) was better though not significantly different from WMS (73%). The specificity of WMS (77%) was similar to the SRI parameters. Combination of WMS and SRI parameters augmented the sensitivity for prediction of functional recovery above WMS alone (82% versus 73%, P=0.015; area under the curve=0.88 versus 0.73, P<0.001), although specificities were comparable (80% versus 77%, P=0.2).
Conclusions— The measurement of low-dose DbE SR and SR is feasible, and their combination with WMS assessment improves the sensitivity of viability assessment with DbE.
Key Words: heart failure echocardiography imaging myocardial infarction stress
Introduction
Evidence of residual viable tissue within the infarct zone has been reported in &50% of segments after myocardial infarction (MI),1 implying a potential for recovery2–5 and prognostic benefit after revascularization.6–9 Prediction of functional recovery, based on detection of contractile reserve with dobutamine echocardiography (DbE), is of comparable accuracy to alternative techniques, including myocardial perfusion imaging, metabolic imaging with conventional scintigraphy, and positron emission tomography.10 However, although DbE is a widely available and low-cost approach for the detection of viable myocardium, its assessment remains subjective and relies on semiquantitative evaluation of endocardial excursion and wall thickening, which requires adequate training of the observer.11
Editorial p 3820
Strain-rate imaging (SRI) is based on the determination of gradients of myocardial velocity between 2 points in space.12 SR and its integral, strain, have been validated as methods to quantify regional myocardial function.13,14 Although a number of animal studies have examined the relation of both resting SRI and its Db response with evidence of viability after MI,15–17 only one human study has validated the technique as a clinical tool, and that study correlated the Db response with metabolic evidence of viability by positron emission tomography.18 Therefore, we sought to assess the feasibility and accuracy of SRI and strain during DbE for the prediction of functional recovery in patients undergoing revascularization after MI, its incremental value to conventional wall-motion scoring (WMS), and the optimal SRI parameter for this purpose.
Methods
Study Design
We performed SRI in all patients presenting to the echocardiography laboratory for DbE assessment of myocardial viability in the context of left ventricular (LV) dysfunction due to previous MI (>6 weeks before). Fifty-five consecutive patients (mean age, 64±10 years; 9 women; mean ejection fraction [EF], 36±8%) who subsequently underwent revascularization by percutaneous coronary intervention or coronary artery bypass grafting were entered into the study. Functional recovery was assessed on a follow-up 2D echocardiogram performed 9 months after revascularization (Figure 1).
Db Stress Echocardiography
Images were obtained with a standard commercial echocardiography system (Vivid Five or Seven, GE Vingmed) and were stored digitally and on tape for subsequent analysis. Parasternal long-axis and short-axis views, as well as 3 standard apical views (4 chamber, 2 chamber, and long axis) were acquired at rest and at each stage during the Db stress study. The LV was divided according to the 16-segment model of the American Society of Echocardiography. A standard Db-atropine stress protocol was performed, starting at a Db infusion rate of 5 μg · kg–1 · min–1 and increasing every 3 minutes to 10, 20, 30, and 40 μg · kg–1 · min–1.19 When 85% of age-predicted maximal heart rate was not achieved and the test result was negative, atropine was given in 0.25-mg increments up to a maximum of 1.2 mg until the target heart rate was achieved. Blood pressure and a 12-lead ECG were recorded at baseline and at the end of every stage.
Two independent observers, blinded to the patients’ clinical data, used both side-by-side digital displays and videotape to score each LV segment at rest and during Db stimulation as 1=normokinetic, 1.5=mildly hypokinetic, 2=moderate to severely hypokinetic, 3=akinetic, or 4=dyskinetic. A segment was considered viable if it improved by at least 1 grade with low-dose Db infusion (5 to 10 μg · kg–1 · min–1). The viable response could either be uniphasic (sustained improvement at peak Db dose) or biphasic (subsequent worsening of WMS at peak Db dose). Patients were considered to have global myocardial viability if 4 or more segments demonstrated improvement (uniphasic or biphasic response) during DbE, based on previous studies demonstrating that this is associated with a significant improvement in LVEF after revascularization.20
Strain Rate Imaging
SRI was performed from the apical long-axis and 2- and 4-chamber views during gray-scale image acquisition at rest and after each stage of DbE. This technique uses color tissue Doppler velocity measurements in each pixel of a sample line to determine spatial velocity gradients along the ultrasound beam according to the equation SR=[v(r)–v(r+r)]/r, as described previously.13 Distance along the ultrasound beam is denoted r and tissue velocity is denoted v. To ensure optimization of signal quality and reduction in signal noise, especially at peak stress, SRI was performed with harmonic imaging and high spatial resolution (24 beams, frame rates varying between 100 and 187 frames per second).21 Images were obtained at each stage, taking care to align the ventricular walls with the ultrasound beam and to obtain the image during breath-hold if possible. At least 3 cardiac cycles were captured and stored digitally.
SR and Strain Measurements
Analysis was performed offline with dedicated software (EchoPAC-PC, GE Vingmed). Measurements were made in each segment of the same model used for WMS, avoiding walls that were poorly visualized, and with insonation angles >30°.22 The region of interest (12x6 mm) was tracked manually in the 2D image on a frame-to-frame basis and maintained in a fixed midmyocardial position to make sure that SR traces represented the same myocardial segment for the whole cardiac cycle.
Tissue velocity measurements were measured at rest and with low-dose Db in 146 segments (in the first 27 patients enrolled into the study), including isovolumic contraction, peak systolic velocity, and time-to-peak (TTP) systolic velocity. The SR and strain measurements used in this study are summarized in Figure 2 and were measured in 369 segments with abnormal resting WM during DbE (55 patients). Peak longitudinal systolic SR was determined as the maximal negative SR within 350 ms after the QRS complex, and isovolumic contraction preceding SR was also documented. Three timing parameters were measured, namely, (1) TTP systolic SR, measured as the difference in time from the end of diastole (corresponding to mitral valve closure, as extracted from the velocity curve and the curved anatomic M mode) to peak SR; (2) time to onset of shortening according to the SR curve, measured as the difference in time from the end of diastole to the onset of negative deflection of the SR curve; and (3) time to end of shortening according to the SR curve, measured as the difference in time from the end of diastole to the zero crossover of the SR curve at the end of systole. End-systolic strain (ESS; the time integral of SR) was measured as the magnitude of strain at aortic valve closure (timed from the velocity curve and curved anatomic M mode). When further shortening occurred after aortic valve closure (end of systole), this was measured as the peak strain (PkS). The difference between ESS and PkS was calculated as the postsystolic shortening (PSS), and from this, the postsystolic index (PSI), expressed as a percentage, was derived from the equation (PSS/PkS)x100.23
Revascularization and Follow-Up
All patients underwent coronary angiography and subsequent revascularization after DbE. The choice of percutaneous or surgical revascularization was based on clinical judgment by the treating physician. Follow-up echocardiography was performed 9 months after revascularization. Segments with resting dysfunction that were adequately revascularized we deemed viable if regional function had improved on side-by-side comparison by observers blinded to the clinical and DbE data. EF was calculated by Simpson’s biplane method for each follow-up study; global functional recovery was identified if the EF had improved by 5% on 2D echocardiography. None of the patients had recurrent angina or clinical events between revascularization and follow-up.
Statistics
Data are expressed as the mean±SD. SPSS for Windows (release 11.0, SPSS Inc) was used for basic statistical analyses, with Stata (version 8, Stata Corp) being used for repeated-measures analyses. Comparisons between segments showing functional recovery at follow-up and those that did not were performed with t tests for continuous variables and 2 tests for categorical variables. The ability of velocity and SRI parameters to predict functional recovery was explored with a random-effects model to address the issue of repeated observations (data on multiple segments per patient used in the analysis). The output from this analysis allowed the derivation of receiver operating characteristic (ROC) curves, which were used to designate cutoffs. However, independent predictors were the same in multivariate models produced by either method, and odds ratios (ORs) for prediction of functional recovery were similar. Multivariate models were performed by forward selection of variables with the likelihood-ratio test for inclusion until the most parsimonious model was found. First-order interaction terms were tested. Goodness of fit was explored with the Hosmer-Lemeshow test, and regression diagnostics were checked. Probability values of P<0.05 were considered statistically significant. The area under the curve (AUC) and ROC curve was calculated for each parameter, and curves were examined to define optimal cutoffs for the prediction of functional recovery. Using these cutpoints, we compared the sensitivity and specificity of WMS with that of SR and ESS parameters for prediction of functional recovery according to the McNemar test.24
Results
Study Group
Table 1 summarizes the clinical characteristics, cardiac risk factors, and current antianginal therapy in the 21 patients who showed global functional recovery (EF baseline versus follow-up, 34±9% versus 47±10%) and the 34 patients who did not (38±8% versus 38±7%). No differences were identified between the groups, who also showed comparable responses to Db stress (Table 2).
Db Stress Echocardiography
A total of 880 segments were evaluated on DbE, of which 369 segments had abnormal resting WM (hypokinetic, akinetic, or dyskinetic). A uniphasic response was identified on WMS in 50 segments (14%), and a biphasic response was present in 107 (29%); 212 segments (57%) showed no augmentation with Db. Of the 369 abnormal segments, we were able to acquire WMS and SRI measurements for 350. Of the 146 (42%) showing functional recovery on follow-up echocardiography, 106 were predicted by WMS (sensitivity, 73%; 95% confidence interval [CI], 68% to 78%). There was no functional recovery in 204 segments (58%), among which WMS predicted failure to recover in 156 (specificity, 77%; 95% CI, 73% to 81%).
Feasibility of SRI and Interobserver Variability
We were able to perform SR and strain analysis in 350 (95%) of the segments with abnormal resting WM. Failure to perform measurements was related to poor visualization of the segment or an insonation angle >30° in 9 segments at rest and in 10 with low-dose Db.
SR and strain analyses were also performed by an independent observer in a total of 40 abnormal segments (5 patients). Table 3 summarizes the interobserver variability for SR, ESS, and timing parameters at rest and with low-dose Db. We evaluated the components of variance with a general linear model and showed that neither patient nor observer factors accounted for a significant proportion of interobserver variability.24 The intraobserver variability for rest and follow-up EF was 2±4%, with similar values for interobserver variability.
Tissue Velocity Measurements
Table 4 summarizes the results of the ability of resting and low-dose DbE tissue velocity measurements in segments to predict functional recovery. None of the tissue velocity measurements were predictive of functional recovery.
Prediction of Functional Recovery With SRI
The resting SRI parameters in segments with and without functional recovery are summarized in Table 5. The only resting SRI parameter predictive of functional recovery was ESS (AUC=0.60). However, resting ESS was not a significant predictor of functional recovery in any of the combined WMS and SRI parameter models, as determined by logistic-regression analysis (see following section).
Table 6 and Figure 3 summarize the low-dose DbE SRI measurements in segments that did and did not recover and that were predictive of functional recovery. The greatest AUCs for the ROC curves were obtained for low-dose Db SR (AUC=0.84, SE=0.02), SR increment (SR) from rest to low-dose Db (AUC=0.82, SE=0.02), low-dose Db ESS (AUC=0.84, SE=0.02), and ESS increment (ESS) from rest to low-dose Db (AUC=0.84, SE=0.03). All of these AUCs significantly exceeded results for WMS (AUC=0.73, SE=0.027; all P<0.001). The AUC for low-dose Db SR was also significantly greater than for SR (P=0.02) and for ESS from rest to low-dose Db (P<0.001). PSI at low-dose Db was significantly lower in segments that recovered compared with those that did not, and the change in PSI from rest to low-dose Db was significantly larger in segments that showed functional recovery. Timing parameters were also different between segments that showed functional recovery and those that did not (Table 6), but the diagnostic content was less, as evidenced by smaller AUCs for the ROC curves.
All low-dose Db SRI measures were predictive of functional recovery in the univariate model, but only low-dose Db SR (OR, 0.16; 95% CI, 0.046 to 0.57; P=0.004) and SR (OR, 0.19; 95% CI, 0.068 to 0.54; P=0.002) were independently predictive in the multivariate model. Table 6 includes the adjusted OR for the prediction of functional recovery by WMS. The unadjusted OR was 8.19 (95% CI, 3.91 to 17.18; P=0.0001).
Comparison of Echocardiographic Techniques for Prediction of Functional Recovery
By applying the optimal cutoff points for SRI parameters from the ROC curves, we compared the sensitivity and specificity of WMS and SRI parameters for the prediction of segmental functional recovery (Figure 4). Compared with WMS (sensitivity, 73%; specificity, 77%), magnitude parameters with low-dose Db were more sensitive but had similar specificity for the prediction of segmental functional recovery. Figure 5 illustrates the improvement in SR and ESS with low-dose Db in a segment that improved (and showed improvement of resting SR and ESS) at follow-up.
Incremental Value of SRI for Prediction of Segmental Functional Recovery
Logistic-regression analysis was used to create a model for prediction of segmental functional recovery based on a combination of WMS and SRI parameters. By using low-dose Db SR and SR increments as continuous variables and WMS as a categorical variable (viable segment=1, nonviable segment=0), we derived a composite score for prediction of recovery: viability score=(1.7xWMS)–(1.8xlow-dose Db SR)–(1.7xSR increment).
By applying a score cutoff of >2.55 (Figures 3 and 4), the model predicted segmental functional recovery with a sensitivity and specificity of 82% (P<0.015) and 80% (P=0.2), respectively, compared with WMS. The AUC for the ROC curve for the viability model (0.882) was significantly greater compared with all other individual SRI parameters and WMS (P<0.001).
Incremental Value of SRI for Prediction of Global Functional Recovery
There were 4 abnormal segments per patient in 47 patients, which allowed us to determine the incremental value of SRI for the prediction of global functional recovery. The presence of 4 segments with enhancement of function by WMS with low-dose Db predicted 15 of the 21 patients who showed global functional recovery, defined by an EF improvement >5% (sensitivity, 71%; 95% CI, 58% to 84%), and predicted failure to recover in 22 of the 26 patients who did not show functional recovery (specificity, 85%; 95% CI, 75% to 95%). The viability model (viability score >2.55 in 4 segments) was similar in sensitivity and specificity in the prediction of global recovery (sensitivity, 67%; 95% CI, 54% to 80%; specificity, 89%; 95% CI, 80% to 97%).
Discussion
The results of this study show that SRI provides a feasible and quantitative technique that is at least comparable in specificity but more sensitive than visual assessment of WMS in the prediction of regional/segmental functional recovery. There is little to choose between the SRI parameters for detection of regional viability, but low-dose Db SR and ESS are the simplest and are less likely to be influenced by noise in the waveforms than is the difference between parameters. A viability model that integrated SRI parameters and WMS gave the best sensitivity and specificity for the prediction of functional recovery, with incremental improvement in sensitivity compared with WMS alone.
DbE Identification of Myocardial Viability
DbE has been widely used for assessment of myocardial viability.10 However, the interpretation of stress echocardiograms is highly subjective and requires special training,25 and even after this, low interinstitutional observer agreement has been described26 and has persisted, despite technical developments.11 A modality allowing objective quantitative analysis of WM and WM response to stress, which can be incorporated into clinical practice, is needed to improve the reproducibility of stress echocardiography. To date, quantitative techniques have been shown to facilitate the identification of abnormal studies,27,28 but little work has been done to facilitate the particularly difficult stress echocardiography application of viability assessment.
SRI and Myocardial Viability
Tissue Doppler imaging has been applied to the detection of myocardial viability with limited success.28 This experience reflects the lack of site specificity of tissue Doppler, in which the velocity of a segment relative to the transducer may be influenced by the behavior of adjacent segments. As expected, none of the tissue velocity measurements in our study were predictive of functional recovery.
SR overcomes these limitations, being little influenced by overall heart motion, cardiac rotation, and motion induced by tethering to adjacent abnormal segments, which can also influence the accuracy of DbE.29,30 Consequently, SRI has been considered to be a more accurate marker than tissue Doppler for the detection of regional myocardial function and has been applied in various animal31–33 and human34–37 studies for the detection of myocardial ischemia and MI.
The ability of SRI to quantify changes in normal myocardial function at varying inotropic states and heart rates was studied in an animal model by Weidemann et al.15,16 From that study, it was concluded that both SR and ESS could quantify changes in myocardial function during clinical stress echocardiography. SR reflected regional contractile function, being uncorrelated with heart rate, whereas ESS was more reflective of EF. In a different animal model, Weidemann et al17 also used SRI to study the regional deformation characteristics of both chronic nontransmural and transmural infarctions before and after Db challenge. Transmural scar extent was correlated closely with ESS at baseline. Nontransmural infarcted myocardium had significantly lower SR and ESS values at baseline, and SR increased with low-dose Db infusion, whereas ESS showed no change. For transmural infarctions, both deformation parameters showed no change during incremental Db infusion.
The only reported clinical application of SRI for the assessment of myocardial viability in patients with depressed LV function after MI was reported by Hoffmann et al.18 That study showed that an increase of peak systolic myocardial SR during low-dose Db stimulation was correlated with evidence of residual metabolic activity, based on the uptake of [18F]deoxyglucose, and could accurately discriminate between different myocardial viability states. However, ESS, postsystolic shortening, and timing parameters were not studied.
Our work builds on that study by comparing the accuracy of various SRI parameters for prediction of functional improvement after revascularization. We identified low-dose Db SR and SR as the most sensitive and specific markers of viability, which is in keeping with previous studies. In addition to this, low-dose Db ESS and ESS were predictive of functional recovery, whereas the timing parameters, PSS, and PSI were less accurate. By integrating these SRI parameters and WMS into a viability model, we were able to increase the sensitivity of the technique for prediction of functional recovery.
Study Limitations
Despite improvements, SRI (more so than its integral, strain) is still limited by signal noise, and both remain angle dependent.22 We tried to minimize these problems by acquiring tissue velocity data with adequate temporal and spatial resolution, as well as taking care that the ventricular walls were aligned with the ultrasound beam within 30° during image acquisition. Finally, we did not attempt to quantify deformation in the different myocardial layers because of concern that lateral resolution was insufficient to acquire this at 16-cm depth in the adult heart. These data therefore reflect average longitudinal deformation across the entire wall and cannot assess the role of the different myocardial layers in the prediction of functional recovery.
Conclusions
The combination of SRI with low-dose DbE is clinically feasible for the detection of myocardial viability and adds incremental value to expert WMS.
Acknowledgments
This study was supported by a project grant (210218) from the National Health and Medical Research Council, Canberra, Australia.
Disclosures
None.
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