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Strain rate analysis allows detection of differences in diastolic function between viable and nonviable myocardial segments
Strain Rate Analysis Allows Detection of Differences in Diastolic Function Between Viable and Nonviable Myocardial Segments Rainer Hoffmann, MD, FESC, Ertunc Altiok, MD, Bernd Nowak, MD, Harald Kühl, MD, Hans-Jürgen Kaiser, MD, Udalrich Buell, MD, and Peter Hanrath, MD, Aachen, Germany
Analysis of diastolic function for assessment of myocardial viability has not been evaluated. Strain rate (SR) analysis allows quantitative segmental analysis of myocardial function and has been used during dobutamine stimulation for assessment of systolic functional reserve. In 37 patients with ischemic left ventricular dysfunction diastolic function was evaluated at rest and during low-dose dobutamine stimulation (10 g/kg/min) using SR imaging and related to F18-fluorodeoxyglucose positron emission tomography. Analysis of peak early (E waves) and late (A waves) diastolic myocardial SR was performed using apical views. In all, 317 segments had normal function at rest by 2-dimensional echocardiography. A total of 192 segments with dyssynergy at rest were classified by positron emission tomography as viable in 94 cases and nonviable in 98 cases. Dyssynergic segments had lower E and A waves SR compared with normal contracting segments. There
The distinction among normal, viable, and nonvia-
ble myocardium in patients with depressed left ventricular (LV) function remains a diagnostic challenge.1 F18-fluorodeoxyglucose (FDG) positron emission tomography (PET) is used as a reference technique for identification of myocardial viability because of its high sensitivity and the possibility of a quantitative analysis.2 Dobutamine stress echocardiography (DSE) with evaluation of systolic myocardial function has been demonstrated to be a reliable alternative for identification of myocardial viability.3 Its major limitation is the observer-dependent subjective visual interpretation of wall motion.4,5 Doppler tissue imaging (DTI) has been used for quantitative evaluation of regional systolic myocardial function at rest and under stress conditions.6-10 The From the Medical Clinic I and Department of Nuclear Medicine (B.N., H-J.K., U.B.), University RWTH Aachen. Presented in part at the American College of Cardiology Scientific Sessions, March 2003, Chicago, Illinois. Reprint requests: Rainer Hoffmann, MD, FESC, Medical Clinic I, University RWTH Aachen, Pauwelsstraße 30, 52057 Aachen, Germany (E-mail: [email protected]). 0894-7317/$30.00 Copyright 2005 by the American Society of Echocardiography. doi:10.1016/j.echo.2004.10.028
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were no significant differences in peak E and A waves SR at rest between dyssynergic viable and nonviable segments. With dobutamine stimulation peak E waves SR increased significantly for viable segments (0.89 ⴞ 0.51-1.06 ⴞ 0.51 L/s, P < .01) whereas it was unchanged for nonviable segments (0.77 ⴞ 0.49-0.78 ⴞ 0.48 L/s, P ⴝ .835). Peak A waves SR increased for viable (0.71 ⴞ 0.55-1.00 ⴞ 0.56 L/s, P < .01) and nonviable (0.57 ⴞ 0.47-0.71 ⴞ 0.58 L/s, P ⴝ .023) segments. However, during dobutamine stimulation peak A waves SR was larger (P < .001) for viable than for nonviable segments. In conclusion, normal contracting segments at rest have higher E and A waves SR compared with dyssynergic segments. Dyssynergic viable myocardial segments demonstrate an increase in E and A waves SR with dobutamine stimulation whereas nonviable segments are less responsive to dobutamine. (J Am Soc Echocardiogr 2005;18:330-5.)
analysis of diastolic function using DTI techniques allows important additional insights into several cardiac pathologies that could not be obtained by systolic function analysis alone.11,12 In combination with dobutamine stimulation the analysis of diastolic function by DTI has been shown to be a sensitive means for the detection of myocardial ischemia.13 Analysis of diastolic function for different myocardial viability states has not been performed. Strain rate (SR) imaging (SRI) is a new technique derived from DTI that allows the determination of velocity gradients between two myocardial points. In contrast to DTI-derived parameters, parameters derived from SRI are not affected by rotation and translation of the whole heart, contraction of adjacent segments, or a basoapical velocity gradient complicating the segmental analysis of function. Thus, SRIderived parameters may be more accurate in the analysis of diastolic function. The objectives of this study were: (1) to evaluate differences in diastolic function between segments with normal or dysfunctional systolic contraction phase; and (2) to determine whether, in the case of LV dysfunction, differences in diastolic function can be identified between viable and nonviable myocardium defined by F18-FDG PET by application of SRI in combination with dobutamine stimulation.
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METHODS Patients A total of 37 patients (61 ⫾ 11 years, 29 men) with reduced LV function because of prior myocardial infarction were included in the study. F18-FDG PET, DSE, and SRI were performed in all patients to evaluate myocardial viability. Furthermore, all patients underwent coronary angiography and cineventriculography. Echocardiography Echocardiograms were done with a system (Vivid Five, General Electric, Horton, Norway) equipped with a 2.5MHz transducer with second harmonic function. Apical long-axis, 2-chamber, and 4-chamber views were acquired as described by the American Society of Echocardiography.14 Dobutamine Echocardiography After baseline echocardiography, dobutamine infusion was started at 5 g/kg/min for 5 minutes followed by 10 g/kg/min for another 5 minutes. Images were acquired continuously on tape and stored digitally at the end of every dose-step. The aim was to observe the monophasic response. Echocardiograms were analyzed using the standard 16-segment model of the American Society of Echocardiography.14 Each segment was scored for both systolic wall thickening and inward wall motion at rest and during dobutamine stimulation. Wall motion was scored as normokinetic, mildly hypokinetic, severely hypokinetic, akinetic, or dyskinetic at rest and at low-dose dobutamine stress. Depending on the contractility at rest and at low-dose dobutamine, segments were described as normal, viable, or nonviable. Normal segments had normal contractility or mild hypokinesia at rest and with low-dose dobutamine stress. Segments were judged to be viable when wall motion in severely hypokinetic, akinetic, or dyskinetic segments improved by at least 1 grade after dobutamine administration. Severe wall-motion abnormality at rest that did not improve with dobutamine infusion identified nonviable segments. SRI SRI is an extension of DTI that determines the velocity gradient between two points along the ultrasound beam. SR is equivalent to the spatial gradient of velocity. It is characterized by the equation: SR ⫽ [v (r) ⫺ v (r ⫹ ⌬r)]/⌬r as described previously.8 An offset of ⌬r ⫽ 1 cm was used in all studies. SRI was performed from the apical long-axis, 4-chamber, and 2-chamber views. Applied to the apical views, this allowed the determination of a basoapical velocity gradient within each segment. The image sector was kept as narrow as possible to achieve the highest possible frame rates. Imaging of only one wall (septum, lateral, posterior, anterior, inferior, anteroseptal) at a time was performed to achieve frame rates of above 140/min with real-time display of SR color images. This approach
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also enabled keeping the angle between the Doppler beam and the longitudinal shortening direction of the wall at less than 30 degrees. Digital data were transferred to the software incorporated in the system (Vivid Five, General Electric, Horton, Norway) for offline analysis. This allowed determination of the SR at any instant during one cardiac cycle for any sample volume. An investigator blinded to the results of 2-dimensional (2D) DSE, cardiac catheterization, and PET determined peak early and late diastolic myocardial SR data of each segment at both rest and low-dose dobutamine. The sample volume was placed in the basal part of each segment halfway between endocardium and epicardium. Autocorrection of sample volume location during systolic contraction was used to account for the inward motion of the ventricular wall to keep the sample volume halfway between endocardium and epicardium. Peak E and A waves SR were determined from 3 consecutive beats to minimize the measurement variability. Cardiac cycles with extrasystolic beats, postextrasystolic beats, or any disturbance of the rhythm were excluded. Repeated analysis of peak systolic SRI data was performed for 30 segments to evaluate the reproducibility of SR data. There was a mean difference between the first and the second analysis of 0.05 ⫾ 0.03 L/s. PET The PET protocol has been described in detail.15 Tc99mtetrofosmin was used as marker of myocardial perfusion and F18-FDG as marker of myocardial metabolism. Myocardial perfusion imaging was done 60 minutes after injection of 370-MBq Tc99m-tetrofosmin using a doublehead gamma camera (Solus, ADAC Laboratories, Milpitas, Calif) with attenuation and scatter corrected reconstruction in a matrix size of 128 ⫻ 128. PET acquisition (ECAT EXACT 922/47, Siemens-CTI, Knoxville, Tenn) was performed on the same day of DSE examination. A total of 185 MBq of F18-FDG were injected. Static emission scans were acquired 45 to 60 minutes after tracer injection. Attenuation-corrected PET data were reconstructed using a Hanning filter (cut-off frequency 0.4) with an axial resolution of 3.325 mm in a matrix size of 128 ⫻ 128. Reoriented tetrofosmin and F18-FDG data were quantified simultaneously by an automatic count-based algorithm using the 16 regions of the echocardiographic model. Tetrofosmin and FDG uptake for each segment were expressed as percentage of the region with the maximal tetrofosmin uptake. Depending on Tc99m-tetrofosmin and F18-FDG tracer uptake, myocardial segments were classified into 3 groups: (1) normal segments defined by a tetrofosmin uptake greater than 70%; (2) mismatch (viable) segments defined by a tetrofosmin uptake 70% or less and a better preserved FDG-uptake (FDG ⫺ tetrofosmin uptake ⱖ 20%); and (3) intermediate and match segments (nonviable) defined by a concordant reduction of both tracers to 70% or less.
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Table Early and late strain rate for different function and myocardial viability states Normal function at rest (n ⴝ 317)
Peak E-wave SR at rest (L/s) Peak E-wave SR with dob (L/s) Change in peak E-wave SR with (L/s) Peak A-wave SR at rest (L/s) Peak A-wave SR with dob (L/s) Change in peak A-wave SR with dob (L/s)
1.13 1.30 0.17 0.98 1.24 0.26
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.58 0.61* 0.58 0.61 0.64* 0.62
Viable by PET (n ⴝ 94)
0.89 1.06 0.17 0.71 1.00 0.29
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.51 0.51* 0.59 0.55 0.56* 0.55
Nonviable by PET (n ⴝ 98)
⬎0.77 0.78 0.01 0.57 0.71 0.14
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.49 0.48† 0.60 0.47 0.58† 0.58
P among all groups
P between viable and nonviable
⬍.001 ⬍.001 .044 ⬍.001 ⬍.001 .068
.103 ⬍.001 .049 .055 ⬍.001 .052
dob, Dobutamine; PET, positron emission tomography; SR, strain rate. *P ⬍ .01 vs rest;†P ⫽ .835 vs rest.
Coronary Angiography and Cineventriculography Coronary angiograms and biplane cineangiograms were stored digitally. The severity of coronary stenosis was determined quantitatively (QuantCor, CASS II, Siemens, Erlangen, Germany). Significant coronary artery stenosis was defined as 50% or more reduction of vessel diameter in at least one major coronary artery. The severity of coronary artery disease was classified as 1-, 2- or 3-vessel disease. Monoplane planimetry of cineventriculograms was performed to determine LV ejection fraction. Statistics Data are expressed as means ⫾ SD. Comparison of continuous variables was performed using paired and unpaired Student t test or analysis of variance as appropriate. Comparison of proportions was performed with the 2 test and the Fisher exact test. A value was considered statistically significant at P ⬍ .05.
RESULTS LV ejection fraction by cineventriculography was 44 ⫾ 10% and fractional area change from the 2D echocardiographic apical 4-chamber view was 29 ⫾ 8%. In all patients a significant coronary artery stenosis (⬎ 50% luminal diameter stenosis) could be documented (3-vessel disease in 16 patients, 2-vessel disease in 11 patients, and 1-vessel disease in 10 patients). Visual assessment of wall motion from the 2D echocardiographic images was possible in 556 of 592 segments (94%). Although 344 segments demonstrated normal function at rest, the remaining 212 segments (38%) were either severely hypokinetic, akinetic, or dyskinetic. F18-FDG PET Considering only the 212 dyssynergic segments at rest, 69 segments (32%) were found to have normal perfusion and metabolism and 35 segments (17%), to be viable with depressed perfusion. These 104 segments were compared with 108 (51%) segments
found to have a match or intermediate finding that were defined as nonviable. Diastolic SR Sampling Analysis of SR samplings was possible in 509 of those segments with 2D wall motion analysis (92%). Analysis of SR samplings was possible in 317 of the 334 segments demonstrating normal function at rest (92%). Considering only those 212 segments with dyssynergy at rest, determination of early and late diastolic SR at rest and during dobutamine stimulation was possible in 192 segments (91%). Peak early and late diastolic SR data at rest and during dobutamine stimulation for the different viability states defined by F18-FDG PET and segments demonstrating normal function at rest are given in Table. Peak E wave SR was significantly smaller for the combined dyssynergic segments at rest compared with the segments demonstrating normal function at rest. There was no difference in E wave SR at rest between viable and nonviable segments defined by F18-FDG PET. During dobutamine stimulation peak E wave SR increased significantly for normal and viable segments whereas it remained unchanged for nonviable segments (Table). Peak A wave SR was also significantly smaller for the combined dyssynergic segments at rest compared with the segments demonstrating normal function at rest. During dobutamine stimulation peak A wave SR increased for normal, viable, and nonviable segments defined by F18-FDG PET. The increase in peak A wave SR tended to be larger for normal and viable segments than for nonviable segments. Considering only dyssynergic segments at rest, peak A wave SR during dobutamine stimulation was larger for viable segments compared with nonviable segments (P ⬍ .001). Figure 1 shows SRI and the analysis of SR curves of a dyssynergic segment found to be viable by F18-FDG PET whereas Figure 2 shows SRI and the analysis of SR curves of a dyssynergic segment found to be nonviable by F18-FDG PET. Considering the 94 segments found to be viable by PET, 63 segments had normal perfusion and
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impaired perfusion. With dobutamine stimulation, peak E-wave SR increased to 1.10 ⫾ 0.47 L/s for segments with normal perfusion whereas it increased to 0.98 ⫾ 0.46 1/s for segments with impaired perfusion (n ⫽ nonsignificant). Peak Awave SR increased to 1.02 ⫾ 0.56 for segments with normal perfusion and to 0.95 ⫾ 0.49 for segments with impaired perfusion (n ⫽ nonsignificant).
DISCUSSION
Figure 1 Strain rate imaging displayed as curved M-mode of one cardiac cycle for septal wall at rest (top) and during dobutamine stimulation (bottom) of severely hypokinetic segment at rest shown to be viable by F18-fluorodeoxyglucose positron emission tomography. Blue color band during early and late diastole becomes more intense and broader during dobutamine stimulation indicating increase of early and late diastolic peak strain rate.
Figure 2 Strain rate imaging displayed as curved M-mode of one cardiac cycle for septal wall at rest (top) and during dobutamine stimulation (bottom) of akinetic segment at rest shown to be nonviable by F18-fluorodeoxyglucose positron emission tomography. There is no change in color for diastolic time period indicating no change in diastolic function.
metabolism whereas 31 segments were viable but had impaired perfusion. There were no differences in peak E-wave SR and peak A-wave SR at rest between those viable segments with normal or
This study demonstrated that: (1) early and late diastolic SR is depressed at rest for severely dyssynergic segments compared with normal contracting segments; and (2) analysis of early and late diastolic SR during dobutamine stimulation demonstrates significant differences between myocardial segments found to be viable or nonviable by F18-FDG PET. Analysis of myocardial viability in patients with depressed LV function is of significant clinical importance as revascularization procedures may improve functional capacity and patient survival.1 The process of 2D DSE has become a widely available and inexpensive method for assessment of myocardial viability.2,3,13 However, visual assessment of myocardial contractility and functional reserve using 2D DSE images is limited by the subjective evaluation process and can be difficult especially in segments adjacent to infarcted areas.4,5 In addition, visual analysis of myocardial function using 2D DSE is confined to analysis of systolic function whereas diastolic function parameters remain undefined. The application of DTI techniques for quantification of systolic ventricular function has been reported in several studies. It has been used for detection of myocardial ischemia and myocardial viability.6,7,13,16,17 Analysis of diastolic function parameters using DTI techniques has been shown to add significant information to the evaluation of systolic function in several cardiac pathologies.11,12,16 In contrast to indices of LV filling, DTI-derived parameters have been proven to be relatively insensitive to the effects of preload compensation18 and they allow a segment-related analysis of diastolic function. Analysis of diastolic function has previously been demonstrated to allow very early and more sensitive detection of coronary artery disease than systolic function analysis.13 Diastolic SRI Derived from color DTI, SRI has recently been introduced as a new real-time imaging modality.8,19 SR is equivalent to the velocity gradient between a point of interest and an adjacent point with a small offset.8 It equals the rate of regional myocardial deformation. SR can be determined by an algorithm that calculates spatial differences in tissue velocities
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between neighboring myocardial regions. The major advantage of SRI compared with DTI is the independence of obtained measurements from the basoapical location of the evaluated segment. Although tissue velocities increase from apex to base because the obtained velocities represent a cumulative velocity of all segments apical to the analyzed segment, SR data are known to be similar for apical, midventricular, and basal segments. Furthermore, in contrast to DTI measurements, SR is not affected by tethering effects from adjacent segments such as rotation or translation of the whole heart.19 The analysis of systolic SR has been used under different clinical settings for a better understanding of cardiac pathologies and understanding of myocardial function.9,10,20-22 This study defined early and late diastolic SR at rest and during dobutamine stimulation for myocardial segments with normal or dysfunctional systolic contraction phase. The results of this study indicate that SRI gives access to the analysis of early and late diastolic function. Segments with dysfunctional systolic contraction phase had also impaired diastolic function parameters. This confirms previous results demonstrating impaired diastolic SR after myocardial infarction23 and is in agreement with previous DTI studies demonstrating a dependence of diastolic function on systolic function.24 This study also demonstrated that nonviable myocardial segments have less diastolic function capacity during dobutamine stimulation compared with viable or normal myocardial segments. The difference in diastolic function capacity affected, in particular, the early diastolic SR. Previous studies have shown that the early diastolic function at rest has an independent predictive value for patient outcome.25 The difference in early diastolic function capacity between viable and nonviable segments may be considered an extension of this previous finding that also relates to the known implications of myocardial viability on clinical outcome. Thus, the evaluation of diastolic function capacity may be used as additional parameter in the assessment of myocardial viability. Study Limitations Urheim et al18 have shown that the analysis of strain by Doppler echocardiography is very angle dependent. Accurate SR data can be expected only if the angle between ultrasonic beam and LV axis is very small. To account for this limitation, SR analysis was performed only for one myocardial wall at a time and the angle between the ultrasonic beam and the LV axis had to be less than 20 degrees. For apical segments, the angle between the ultrasonic beam and the LV axis tends to be greater resulting in greater inaccuracies in the determination of SR for apical segments. The current technology of SRI is characterized by considerable noise artifacts in the
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SR signal. To reduce the impact of this limitation we averaged the SRI results of 3 heartbeats. However, the noise in the SR signal increases with higher heart rates and reduced image quality. Simultaneously, there might be a tendency for fusion of SR E-wave and A-wave with higher heart rates. Thus, in favor of reasonable data quality, we confined the analysis to low-dose dobutamine stress. This study did not focus on the analysis of postsystolic thickening. However, postsystolic thickening should, rather, be considered as an extension of systolic thickening and occurs an earlier instant than the early diastolic SR. Conclusion Dyssynergic myocardial segments demonstrate impaired diastolic function at rest. Early and late diastolic function during dobutamine stimulation is impaired for nonviable segments compared with viable segments. Diastolic SR analysis during dobutamine stimulation may be added to systolic function analysis in the assessment of myocardial viability.
REFERENCES 1. Wijn W, Vatner SF, Camici PG. Mechanisms of disease: hibernating myocardium. N Engl J Med 1998;339:173-81. 2. Bax JJ, Wijns W, Cornel JH, Visser FC, Boersma E, Fioretti PM. Accuracy of currently available techniques for prediction of functional recovery after revascularization in patients with left ventricular dysfunction due to chronic coronary artery disease: comparison of pooled data from the literature. J Am Coll Cardiol 1997;30:1451-60. 3. Pierard LA, De Landsheere CM, Berthe C, Rigo P, Kulbertus HE. Identification of viable myocardium by echocardiography during dobutamine infusion in patients with myocardial infarction after thrombolytic therapy: comparison with positron emission tomography. J Am Coll Cardiol 1990;15:1021-31. 4. Picano E, Lattanzi F, Orlandini A, Marini C, L’Abbate A. Stress echocardiography and the human factor: the importance of being expert. J Am Coll Cardiol 1990;17:666-7. 5. Hoffmann R, Lethen H, Marwick T, Arnese M, Fioretti P, Pingitore A, et al. Analysis of interinstitutional observer agreement in interpretation of dobutamine stress echocardiograms. J Am Coll Cardiol 1996;27:330-6. 6. Wilkenshoff UM, Sovany A, Wigstrom L, Olstad B, Lindstrom L, Engvall J, et al. Regional mean systolic myocardial velocity estimation by real-time color Doppler myocardial imaging: a new technique for quantifying regional systolic function. J Am Soc Echocardiogr 1998;11:683-92. 7. Katz WE, Gulati VK, Mahler CM, Gorcsan J III. Quantitative evaluation of the segmental left ventricular response to dobutamine stress by tissue Doppler echocardiography. Am J Cardiol 1997;79:1036-42. 8. Heimdal A, Stoylen A, Torp H, Skjaerpe T. Real-time strain rate imaging of the left ventricle by ultrasound. J Am Soc Echocardiogr 1998;11:1013-9. 9. Voigt JU, Exner B, Schmiedehausen K, Huchzermeyer C, Reulbach U, Nixdorff U, et al. Strain-rate imaging during dobutamine stress echocardiography provides objective evidence of inducible ischemia. Circulation 2003;107:2120-6.
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10. Hoffmann R, Altiok E, Nowak B, Kühl H, Kaiser HJ, Büll U, et al. Strain rate measurement by Doppler echocardiography allows improved assessment of myocardial viability in patients with depressed left ventricular function. J Am Coll Cardiol 2002;39:443-9. 11. Garcia MJ, Thomas JD, Klein AL. New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865-75. 12. Kato T, Noda A, Izawa H, Nishizawa T, Somura F, Yamada A, et al. Myocardial velocity gradient as a noninvasively determined index of left ventricular diastolic dysfunction in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2003; 42:278-85. 13. von Bibra H, Tuchnitz A, Klein A, Schneider-Eicke J, Schomig A, Schwaiger M. Regional diastolic function by pulsed Doppler myocardial mapping for the detection of left ventricular ischemia during pharmacologic stress testing: a comparison with stress echocardiography and perfusion scintigraphy. J Am Coll Cardiol 2000;36:444-52. 14. Schiller NB, Shah PM, Crawford M, De Maria A, Devereux R, Freigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography: American Society of Echocardiography committee on standards, subcommittee on quantitation of two-dimensional echocardiograms. J Am Soc Echocardiogr 1989;2:358-67. 15. vom Dahl J, Altehoefer C, Sheehan FH, Buechin P, Uebis R, Messmer BJ, et al. Recovery of regional left ventricular dysfunction after coronary revascularization. J Am Coll Cardiol 1996;28:948-58. 16. Garot J, Derumeaux GA, Monin JL, Duval-Moulin AM, Simon M, Pascal D, et al. Quantitative systolic and diastolic transmyocardial velocity gradients assessed by M-mode colour Doppler tissue imaging as reliable indicators of regional left ventricular function after acute myocardial infarction. Eur Heart J 1999;20:593-603. 17. Rambaldi R, Poldermans D, Bax JJ, Boersma E, Elhendy A, Vletter W, et al. Doppler tissue velocity sampling improves diag-
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nostic accuracy during dobutamine stress echocardiography for the assessment of viable myocardium in patients with severe left ventricular dysfunction. Eur Heart J 2000;21:1091-8. Oki T, Tabata T, Yamada H, Wakatsuki T, Shinohara H, Nishikado A, et al. Clinical application of pulsed Doppler tissue imaging for assessing abnormal left ventricular relaxation. Am J Cardiol 1997;79:921-8. Urheim S, Edvardsen T, Torp H, Angelsen B, Smiseth OA. Myocardial strain by Doppler echocardiography: validation of a new method to quantify regional myocardial function. Circulation 2000;102:1158-5. Kukulski T, Jamal F, Herbots L, D’hooge J, Bijnens B, Hatle L, et al. Identification of acutely ischemic myocardium using ultrasonic strain measurements: a clinical study in patients undergoing coronary angioplasty. J Am Coll Cardiol 2003; 41:810-9. Edvardsen T, Skulstad H, Aakhus S, Urheim S, Ihlen H. Regional myocardial systolic function during acute myocardial ischemia assessed by strain Doppler echocardiography. J Am Coll Cardiol 2001;37:726-30. Götte MJW, van Rossum AC, Twisk JWR, Kuijer JPA, Marcus T, Visser CA. Quantification of regional contractile function after infarction: strain analysis superior to wall thickening analysis in discriminating infarct from remote myocardium. J Am Coll Cardiol 2001;37:808-17. Derumeaux G, Loufoua J, Pontier G, Cribier A, Ovize M. Tissue Doppler imaging differentiates transmural from nontransmural acute myocardial infarction after reperfusion therapy. Circulation 2001;103:589-96. Yip G, Wang M, Zhang Y, Fung JW, Ho PY, Sanderson JE. Left ventricular long axis function in diastolic heart failure is reduced in both diastole and systole: time for a redefinition? Heart 2002;87:121-5. Wang M, Yip GW, Wang AY, Zhang Y, Ho PY, Tse MK, et al. Peak early diastolic mitral annulus velocity by tissue Doppler imaging adds independent and incremental prognostic value. J Am Coll Cardiol 2003;41:820-6.
Analysis of diastolic function for assessment of myocardial viability has not been evaluated. Strain rate (SR) analysis allows quantitative segmental analysis of myocardial function and has been used during dobutamine stimulation for assessment of systolic functional reserve. In 37 patients with ischemic left ventricular dysfunction diastolic function was evaluated at rest and during low-dose dobutamine stimulation (10 g/kg/min) using SR imaging and related to F18-fluorodeoxyglucose positron emission tomography. Analysis of peak early (E waves) and late (A waves) diastolic myocardial SR was performed using apical views. In all, 317 segments had normal function at rest by 2-dimensional echocardiography. A total of 192 segments with dyssynergy at rest were classified by positron emission tomography as viable in 94 cases and nonviable in 98 cases. Dyssynergic segments had lower E and A waves SR compared with normal contracting segments. There
The distinction among normal, viable, and nonvia-
ble myocardium in patients with depressed left ventricular (LV) function remains a diagnostic challenge.1 F18-fluorodeoxyglucose (FDG) positron emission tomography (PET) is used as a reference technique for identification of myocardial viability because of its high sensitivity and the possibility of a quantitative analysis.2 Dobutamine stress echocardiography (DSE) with evaluation of systolic myocardial function has been demonstrated to be a reliable alternative for identification of myocardial viability.3 Its major limitation is the observer-dependent subjective visual interpretation of wall motion.4,5 Doppler tissue imaging (DTI) has been used for quantitative evaluation of regional systolic myocardial function at rest and under stress conditions.6-10 The From the Medical Clinic I and Department of Nuclear Medicine (B.N., H-J.K., U.B.), University RWTH Aachen. Presented in part at the American College of Cardiology Scientific Sessions, March 2003, Chicago, Illinois. Reprint requests: Rainer Hoffmann, MD, FESC, Medical Clinic I, University RWTH Aachen, Pauwelsstraße 30, 52057 Aachen, Germany (E-mail: [email protected]). 0894-7317/$30.00 Copyright 2005 by the American Society of Echocardiography. doi:10.1016/j.echo.2004.10.028
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were no significant differences in peak E and A waves SR at rest between dyssynergic viable and nonviable segments. With dobutamine stimulation peak E waves SR increased significantly for viable segments (0.89 ⴞ 0.51-1.06 ⴞ 0.51 L/s, P < .01) whereas it was unchanged for nonviable segments (0.77 ⴞ 0.49-0.78 ⴞ 0.48 L/s, P ⴝ .835). Peak A waves SR increased for viable (0.71 ⴞ 0.55-1.00 ⴞ 0.56 L/s, P < .01) and nonviable (0.57 ⴞ 0.47-0.71 ⴞ 0.58 L/s, P ⴝ .023) segments. However, during dobutamine stimulation peak A waves SR was larger (P < .001) for viable than for nonviable segments. In conclusion, normal contracting segments at rest have higher E and A waves SR compared with dyssynergic segments. Dyssynergic viable myocardial segments demonstrate an increase in E and A waves SR with dobutamine stimulation whereas nonviable segments are less responsive to dobutamine. (J Am Soc Echocardiogr 2005;18:330-5.)
analysis of diastolic function using DTI techniques allows important additional insights into several cardiac pathologies that could not be obtained by systolic function analysis alone.11,12 In combination with dobutamine stimulation the analysis of diastolic function by DTI has been shown to be a sensitive means for the detection of myocardial ischemia.13 Analysis of diastolic function for different myocardial viability states has not been performed. Strain rate (SR) imaging (SRI) is a new technique derived from DTI that allows the determination of velocity gradients between two myocardial points. In contrast to DTI-derived parameters, parameters derived from SRI are not affected by rotation and translation of the whole heart, contraction of adjacent segments, or a basoapical velocity gradient complicating the segmental analysis of function. Thus, SRIderived parameters may be more accurate in the analysis of diastolic function. The objectives of this study were: (1) to evaluate differences in diastolic function between segments with normal or dysfunctional systolic contraction phase; and (2) to determine whether, in the case of LV dysfunction, differences in diastolic function can be identified between viable and nonviable myocardium defined by F18-FDG PET by application of SRI in combination with dobutamine stimulation.
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METHODS Patients A total of 37 patients (61 ⫾ 11 years, 29 men) with reduced LV function because of prior myocardial infarction were included in the study. F18-FDG PET, DSE, and SRI were performed in all patients to evaluate myocardial viability. Furthermore, all patients underwent coronary angiography and cineventriculography. Echocardiography Echocardiograms were done with a system (Vivid Five, General Electric, Horton, Norway) equipped with a 2.5MHz transducer with second harmonic function. Apical long-axis, 2-chamber, and 4-chamber views were acquired as described by the American Society of Echocardiography.14 Dobutamine Echocardiography After baseline echocardiography, dobutamine infusion was started at 5 g/kg/min for 5 minutes followed by 10 g/kg/min for another 5 minutes. Images were acquired continuously on tape and stored digitally at the end of every dose-step. The aim was to observe the monophasic response. Echocardiograms were analyzed using the standard 16-segment model of the American Society of Echocardiography.14 Each segment was scored for both systolic wall thickening and inward wall motion at rest and during dobutamine stimulation. Wall motion was scored as normokinetic, mildly hypokinetic, severely hypokinetic, akinetic, or dyskinetic at rest and at low-dose dobutamine stress. Depending on the contractility at rest and at low-dose dobutamine, segments were described as normal, viable, or nonviable. Normal segments had normal contractility or mild hypokinesia at rest and with low-dose dobutamine stress. Segments were judged to be viable when wall motion in severely hypokinetic, akinetic, or dyskinetic segments improved by at least 1 grade after dobutamine administration. Severe wall-motion abnormality at rest that did not improve with dobutamine infusion identified nonviable segments. SRI SRI is an extension of DTI that determines the velocity gradient between two points along the ultrasound beam. SR is equivalent to the spatial gradient of velocity. It is characterized by the equation: SR ⫽ [v (r) ⫺ v (r ⫹ ⌬r)]/⌬r as described previously.8 An offset of ⌬r ⫽ 1 cm was used in all studies. SRI was performed from the apical long-axis, 4-chamber, and 2-chamber views. Applied to the apical views, this allowed the determination of a basoapical velocity gradient within each segment. The image sector was kept as narrow as possible to achieve the highest possible frame rates. Imaging of only one wall (septum, lateral, posterior, anterior, inferior, anteroseptal) at a time was performed to achieve frame rates of above 140/min with real-time display of SR color images. This approach
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also enabled keeping the angle between the Doppler beam and the longitudinal shortening direction of the wall at less than 30 degrees. Digital data were transferred to the software incorporated in the system (Vivid Five, General Electric, Horton, Norway) for offline analysis. This allowed determination of the SR at any instant during one cardiac cycle for any sample volume. An investigator blinded to the results of 2-dimensional (2D) DSE, cardiac catheterization, and PET determined peak early and late diastolic myocardial SR data of each segment at both rest and low-dose dobutamine. The sample volume was placed in the basal part of each segment halfway between endocardium and epicardium. Autocorrection of sample volume location during systolic contraction was used to account for the inward motion of the ventricular wall to keep the sample volume halfway between endocardium and epicardium. Peak E and A waves SR were determined from 3 consecutive beats to minimize the measurement variability. Cardiac cycles with extrasystolic beats, postextrasystolic beats, or any disturbance of the rhythm were excluded. Repeated analysis of peak systolic SRI data was performed for 30 segments to evaluate the reproducibility of SR data. There was a mean difference between the first and the second analysis of 0.05 ⫾ 0.03 L/s. PET The PET protocol has been described in detail.15 Tc99mtetrofosmin was used as marker of myocardial perfusion and F18-FDG as marker of myocardial metabolism. Myocardial perfusion imaging was done 60 minutes after injection of 370-MBq Tc99m-tetrofosmin using a doublehead gamma camera (Solus, ADAC Laboratories, Milpitas, Calif) with attenuation and scatter corrected reconstruction in a matrix size of 128 ⫻ 128. PET acquisition (ECAT EXACT 922/47, Siemens-CTI, Knoxville, Tenn) was performed on the same day of DSE examination. A total of 185 MBq of F18-FDG were injected. Static emission scans were acquired 45 to 60 minutes after tracer injection. Attenuation-corrected PET data were reconstructed using a Hanning filter (cut-off frequency 0.4) with an axial resolution of 3.325 mm in a matrix size of 128 ⫻ 128. Reoriented tetrofosmin and F18-FDG data were quantified simultaneously by an automatic count-based algorithm using the 16 regions of the echocardiographic model. Tetrofosmin and FDG uptake for each segment were expressed as percentage of the region with the maximal tetrofosmin uptake. Depending on Tc99m-tetrofosmin and F18-FDG tracer uptake, myocardial segments were classified into 3 groups: (1) normal segments defined by a tetrofosmin uptake greater than 70%; (2) mismatch (viable) segments defined by a tetrofosmin uptake 70% or less and a better preserved FDG-uptake (FDG ⫺ tetrofosmin uptake ⱖ 20%); and (3) intermediate and match segments (nonviable) defined by a concordant reduction of both tracers to 70% or less.
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Table Early and late strain rate for different function and myocardial viability states Normal function at rest (n ⴝ 317)
Peak E-wave SR at rest (L/s) Peak E-wave SR with dob (L/s) Change in peak E-wave SR with (L/s) Peak A-wave SR at rest (L/s) Peak A-wave SR with dob (L/s) Change in peak A-wave SR with dob (L/s)
1.13 1.30 0.17 0.98 1.24 0.26
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.58 0.61* 0.58 0.61 0.64* 0.62
Viable by PET (n ⴝ 94)
0.89 1.06 0.17 0.71 1.00 0.29
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.51 0.51* 0.59 0.55 0.56* 0.55
Nonviable by PET (n ⴝ 98)
⬎0.77 0.78 0.01 0.57 0.71 0.14
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.49 0.48† 0.60 0.47 0.58† 0.58
P among all groups
P between viable and nonviable
⬍.001 ⬍.001 .044 ⬍.001 ⬍.001 .068
.103 ⬍.001 .049 .055 ⬍.001 .052
dob, Dobutamine; PET, positron emission tomography; SR, strain rate. *P ⬍ .01 vs rest;†P ⫽ .835 vs rest.
Coronary Angiography and Cineventriculography Coronary angiograms and biplane cineangiograms were stored digitally. The severity of coronary stenosis was determined quantitatively (QuantCor, CASS II, Siemens, Erlangen, Germany). Significant coronary artery stenosis was defined as 50% or more reduction of vessel diameter in at least one major coronary artery. The severity of coronary artery disease was classified as 1-, 2- or 3-vessel disease. Monoplane planimetry of cineventriculograms was performed to determine LV ejection fraction. Statistics Data are expressed as means ⫾ SD. Comparison of continuous variables was performed using paired and unpaired Student t test or analysis of variance as appropriate. Comparison of proportions was performed with the 2 test and the Fisher exact test. A value was considered statistically significant at P ⬍ .05.
RESULTS LV ejection fraction by cineventriculography was 44 ⫾ 10% and fractional area change from the 2D echocardiographic apical 4-chamber view was 29 ⫾ 8%. In all patients a significant coronary artery stenosis (⬎ 50% luminal diameter stenosis) could be documented (3-vessel disease in 16 patients, 2-vessel disease in 11 patients, and 1-vessel disease in 10 patients). Visual assessment of wall motion from the 2D echocardiographic images was possible in 556 of 592 segments (94%). Although 344 segments demonstrated normal function at rest, the remaining 212 segments (38%) were either severely hypokinetic, akinetic, or dyskinetic. F18-FDG PET Considering only the 212 dyssynergic segments at rest, 69 segments (32%) were found to have normal perfusion and metabolism and 35 segments (17%), to be viable with depressed perfusion. These 104 segments were compared with 108 (51%) segments
found to have a match or intermediate finding that were defined as nonviable. Diastolic SR Sampling Analysis of SR samplings was possible in 509 of those segments with 2D wall motion analysis (92%). Analysis of SR samplings was possible in 317 of the 334 segments demonstrating normal function at rest (92%). Considering only those 212 segments with dyssynergy at rest, determination of early and late diastolic SR at rest and during dobutamine stimulation was possible in 192 segments (91%). Peak early and late diastolic SR data at rest and during dobutamine stimulation for the different viability states defined by F18-FDG PET and segments demonstrating normal function at rest are given in Table. Peak E wave SR was significantly smaller for the combined dyssynergic segments at rest compared with the segments demonstrating normal function at rest. There was no difference in E wave SR at rest between viable and nonviable segments defined by F18-FDG PET. During dobutamine stimulation peak E wave SR increased significantly for normal and viable segments whereas it remained unchanged for nonviable segments (Table). Peak A wave SR was also significantly smaller for the combined dyssynergic segments at rest compared with the segments demonstrating normal function at rest. During dobutamine stimulation peak A wave SR increased for normal, viable, and nonviable segments defined by F18-FDG PET. The increase in peak A wave SR tended to be larger for normal and viable segments than for nonviable segments. Considering only dyssynergic segments at rest, peak A wave SR during dobutamine stimulation was larger for viable segments compared with nonviable segments (P ⬍ .001). Figure 1 shows SRI and the analysis of SR curves of a dyssynergic segment found to be viable by F18-FDG PET whereas Figure 2 shows SRI and the analysis of SR curves of a dyssynergic segment found to be nonviable by F18-FDG PET. Considering the 94 segments found to be viable by PET, 63 segments had normal perfusion and
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impaired perfusion. With dobutamine stimulation, peak E-wave SR increased to 1.10 ⫾ 0.47 L/s for segments with normal perfusion whereas it increased to 0.98 ⫾ 0.46 1/s for segments with impaired perfusion (n ⫽ nonsignificant). Peak Awave SR increased to 1.02 ⫾ 0.56 for segments with normal perfusion and to 0.95 ⫾ 0.49 for segments with impaired perfusion (n ⫽ nonsignificant).
DISCUSSION
Figure 1 Strain rate imaging displayed as curved M-mode of one cardiac cycle for septal wall at rest (top) and during dobutamine stimulation (bottom) of severely hypokinetic segment at rest shown to be viable by F18-fluorodeoxyglucose positron emission tomography. Blue color band during early and late diastole becomes more intense and broader during dobutamine stimulation indicating increase of early and late diastolic peak strain rate.
Figure 2 Strain rate imaging displayed as curved M-mode of one cardiac cycle for septal wall at rest (top) and during dobutamine stimulation (bottom) of akinetic segment at rest shown to be nonviable by F18-fluorodeoxyglucose positron emission tomography. There is no change in color for diastolic time period indicating no change in diastolic function.
metabolism whereas 31 segments were viable but had impaired perfusion. There were no differences in peak E-wave SR and peak A-wave SR at rest between those viable segments with normal or
This study demonstrated that: (1) early and late diastolic SR is depressed at rest for severely dyssynergic segments compared with normal contracting segments; and (2) analysis of early and late diastolic SR during dobutamine stimulation demonstrates significant differences between myocardial segments found to be viable or nonviable by F18-FDG PET. Analysis of myocardial viability in patients with depressed LV function is of significant clinical importance as revascularization procedures may improve functional capacity and patient survival.1 The process of 2D DSE has become a widely available and inexpensive method for assessment of myocardial viability.2,3,13 However, visual assessment of myocardial contractility and functional reserve using 2D DSE images is limited by the subjective evaluation process and can be difficult especially in segments adjacent to infarcted areas.4,5 In addition, visual analysis of myocardial function using 2D DSE is confined to analysis of systolic function whereas diastolic function parameters remain undefined. The application of DTI techniques for quantification of systolic ventricular function has been reported in several studies. It has been used for detection of myocardial ischemia and myocardial viability.6,7,13,16,17 Analysis of diastolic function parameters using DTI techniques has been shown to add significant information to the evaluation of systolic function in several cardiac pathologies.11,12,16 In contrast to indices of LV filling, DTI-derived parameters have been proven to be relatively insensitive to the effects of preload compensation18 and they allow a segment-related analysis of diastolic function. Analysis of diastolic function has previously been demonstrated to allow very early and more sensitive detection of coronary artery disease than systolic function analysis.13 Diastolic SRI Derived from color DTI, SRI has recently been introduced as a new real-time imaging modality.8,19 SR is equivalent to the velocity gradient between a point of interest and an adjacent point with a small offset.8 It equals the rate of regional myocardial deformation. SR can be determined by an algorithm that calculates spatial differences in tissue velocities
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between neighboring myocardial regions. The major advantage of SRI compared with DTI is the independence of obtained measurements from the basoapical location of the evaluated segment. Although tissue velocities increase from apex to base because the obtained velocities represent a cumulative velocity of all segments apical to the analyzed segment, SR data are known to be similar for apical, midventricular, and basal segments. Furthermore, in contrast to DTI measurements, SR is not affected by tethering effects from adjacent segments such as rotation or translation of the whole heart.19 The analysis of systolic SR has been used under different clinical settings for a better understanding of cardiac pathologies and understanding of myocardial function.9,10,20-22 This study defined early and late diastolic SR at rest and during dobutamine stimulation for myocardial segments with normal or dysfunctional systolic contraction phase. The results of this study indicate that SRI gives access to the analysis of early and late diastolic function. Segments with dysfunctional systolic contraction phase had also impaired diastolic function parameters. This confirms previous results demonstrating impaired diastolic SR after myocardial infarction23 and is in agreement with previous DTI studies demonstrating a dependence of diastolic function on systolic function.24 This study also demonstrated that nonviable myocardial segments have less diastolic function capacity during dobutamine stimulation compared with viable or normal myocardial segments. The difference in diastolic function capacity affected, in particular, the early diastolic SR. Previous studies have shown that the early diastolic function at rest has an independent predictive value for patient outcome.25 The difference in early diastolic function capacity between viable and nonviable segments may be considered an extension of this previous finding that also relates to the known implications of myocardial viability on clinical outcome. Thus, the evaluation of diastolic function capacity may be used as additional parameter in the assessment of myocardial viability. Study Limitations Urheim et al18 have shown that the analysis of strain by Doppler echocardiography is very angle dependent. Accurate SR data can be expected only if the angle between ultrasonic beam and LV axis is very small. To account for this limitation, SR analysis was performed only for one myocardial wall at a time and the angle between the ultrasonic beam and the LV axis had to be less than 20 degrees. For apical segments, the angle between the ultrasonic beam and the LV axis tends to be greater resulting in greater inaccuracies in the determination of SR for apical segments. The current technology of SRI is characterized by considerable noise artifacts in the
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SR signal. To reduce the impact of this limitation we averaged the SRI results of 3 heartbeats. However, the noise in the SR signal increases with higher heart rates and reduced image quality. Simultaneously, there might be a tendency for fusion of SR E-wave and A-wave with higher heart rates. Thus, in favor of reasonable data quality, we confined the analysis to low-dose dobutamine stress. This study did not focus on the analysis of postsystolic thickening. However, postsystolic thickening should, rather, be considered as an extension of systolic thickening and occurs an earlier instant than the early diastolic SR. Conclusion Dyssynergic myocardial segments demonstrate impaired diastolic function at rest. Early and late diastolic function during dobutamine stimulation is impaired for nonviable segments compared with viable segments. Diastolic SR analysis during dobutamine stimulation may be added to systolic function analysis in the assessment of myocardial viability.
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