Tissue Doppler imaging for the diagnosis of coronary artery disease Otto A. Smiseth a , Asbjorn Stoylen b and Halfdan Ihlen a Purpose of review Tissue Doppler imaging (TDI) is a diagnostic method that provides quantitative data about myocardial function. The present review discusses the most recent developments in the application of TDI in coronary artery disease. Recent findings The most widely used TDI modality is velocity imaging, and systolic function is measured as peak velocity during LV ejection. Several recent studies show that TDI measurements during the LV isovolumic phases provide unique information regarding myocardial dysfunction. Since velocity imaging is confounded by influence from velocities in other segments, the TDI-based modalities strain- and strain rate imaging (SRI) have been introduced to measure regional shortening fraction and shortening rate, respectively. Velocity imaging during stress echocardiography has been validated clinically and appears equivalent, but not superior to conventional visual assessment of grey scale images. Potentially, more comprehensive evaluation that includes the use of SRI may improve the diagnostic power of TDI further. Preliminary reports suggest that TDI may have an important role in the assessment of viability in acute coronary occlusion, but this needs to be demonstrated in appropriately designed clinical trials. Summary At the present time tissue Doppler velocity imaging can be recommended for clinical use, especially the pulsed mode. Strain rate imaging may be useful as additional imaging, but needs further refinement before it is ready for routine clinical use. Keywords echocardiography, tissue Doppler, coronary artery disease, acute myocardial infarction Curr Opin Cardiol 19:421–429. © 2004 Lippincott Williams & Wilkins. Introduction In clinical practice left ventricular (LV) function is com- monly evaluated by 2-D and M-mode echocardiography. These modalities have significant limitations, and tissue Doppler imaging (TDI) has been introduced as a quan- titative and more objective method for assessing myocar- dial function. The TDI modalities include myocardial velocity imaging, displacement imaging, strain rate im- aging, and strain imaging (Fig. 1). This review discusses the most recent developments in TDI-based cardiac di- agnostics, and discusses how TDI may be applied in the evaluation of patients with acute myocardial infarction as well as chronic coronary artery disease. Velocity imaging As with Doppler flow, tissue Doppler (TDI) measures velocities by the Doppler shift of reflected ultrasound. The signals are of low velocity and high intensity, and are obtained with low pass filtering and low gain. Veloc- ities are measured in the conventional imaging planes, from apical views as longitudinal velocities and from parasternal views as radial velocities. Velocities can be obtained using pulsed Doppler or color Doppler mode [1]. Pulsed Doppler measures velocities in one sample volume at a time by spectral analysis. Due to short pulse length, the spectrum is broad relative to the velocity scale. This implies that peak velocities may be substantially higher than mean velocities, typically about 25% higher [2]. The method is on line, relatively robust, easy to use, and quick. Color Doppler samples the velocities of all pixels in the sector nearly simultaneously, and by post processing ve- locities in different parts of the ventricle can be mea- sured on the same image (Fig. 1). Velocities are obtained by autocorrelation, which gives mean values. By per- forming temporal integration of velocities from a particu- lar region one obtains displacement curves. In long-axis views velocity and displacement increase progressively from apex towards base. Color coding of the displace- ment values in the image has been proposed as an easy approach to detect regional myocardial dysfunction at rest and during stress echocardiography [3,4], but the technique needs further clinical testing. When myocardial velocities are measured by TDI the transducer represents a fixed extracardiac reference a Department of Cardiology, Rikshospitalet University Hospital, Oslo, Norway and b NTNU, Trondheim, Norway Correspondence to Otto A. Smiseth, Department of Cardiology, Rikshospitalet, N-0027 Oslo, Norway Tel: 4723070000; e-mail: o.a.smiseth@klinmed.uio.no Current Opinion in Cardiology 2004, 19:421–429 © 2004 Lippincott Williams & Wilkins 0268-4705 421 point, and the velocities within a myocardial segment is the net result of motion caused by contractions in that segment, motion due to tethering to other segments, and overall motion of the heart. The effect of tethering ex- plains why left ventricular (LV) longitudinal velocities measured from an apical window, increase progressively from the apex towards the base. During the cardiac cycle the ventricular apex is relatively stationary, while the mitral ring moves towards and away from the apex during systole and diastole, respectively. Therefore, mitral ring motion is in essence the sum of all longitudinal shorten- ing and lengthening between the apex and the base. Thus, ischemia in the apical region causes reduced myo- cardial velocities not only in the apex, but also in the nonischemic basal portion of the ventricle [2,5]. Impor- tantly, the reduced TDI velocities in basal segments do not mean there is a reduction in function in these seg- ments. Likewise, due to tethering, contractions in non- ischemic regions may cause velocities in neighboring ischemic regions, and accordingly nonviable myocardium appears to contract [2,5,6]. The recently introduced TDI modalities strain and strain rate imaging (SRI) may help to overcome these limitations. Strain- and strain rate imaging Strain means deformation and strain rate means deforma- tion rate [7]. Myocardial strain rate reflects how fast re- gional myocardial shortening or lengthening occurs, and is calculated from myocardial Doppler velocities (V 1 and V 2 ) measured at two locations separated by a distance (L) [8]. Strain rate equals the instantaneous spatial velocity gradient and has units of sec -1 :SR=(V 2 -V 1 )/L. Some authors present the measurements as velocity gradient in- stead of strain rate [9]. When V 1 and V 2 are different there is deformation of the tissue in between. In the case that the two locations are getting closer there is myocar- dial shortening, and when they move apart there is lengthening. Strain is calculated as the time integral of strain rate, most often using end-diastole as reference, and is a di- mensionless quantity [5]. In clinical terms strain repre- Figure 1. Tissue Doppler recordings from septum of a normal subject in a long axis view The left column shows velocity tracings, with positive velocities towards the apex in systole, away from the apex in diastole. The second column shows displacement curves obtained by temporal integration of the velocity curves. The third column shows strain rate, obtained by a spatial derivation of velocity data. Strain rate is negative in systole (shortening) and positive in diastole (lengthening). The right column shows strain, obtained by temporal integration of strain rate. The time axis is the same for all modalities. Velocity and displacement decrease from base to apex, whereas strain and strain rate are similar in magnitude at all levels. 422 Imaging and echocardiography sents regional myocardial shortening fraction when mea- surements are done in the LV long axis, and thickening fraction, in the short axis. Alternatively one may report strain values as percentage shortening and percentage thicken- ing. Strain rate represents regional myocardial shortening rate and thickening rate, respectively. Although strain and strain rate are load dependent [5] this is not a major limitation in the assessment of coro- nary artery disease, since finding of regional differences is more important than absolute values. Methodological limitations of strain rate imaging Since strain rate represents a difference between two velocities there is a significant problem with random noise. The signal-to-noise ratio can be improved by in- creasing the offset distance (strain length), which in- creases the velocity difference. The problem with ran- dom noise can also be reduced by temporal averaging within a heart cycle, and by averaging of multiple heart cycles. However, these methods for noise reduction rep- resent compromises between optimal signal-to-noise ra- tio and requirements for spatial and temporal resolution. Semiquantitative information can be obtained directly from the color tissue recordings, and reduces the impor- tance of noise. The derived curved color M-mode and 3-D color strain images (Fig. 2) give a visual presentation of data and may separate between true pathology and artefacts [10]. Another problem with strain rate imaging is strong sen- sitivity to misalignment between the cardiac axis and the echo beam. Strains in the long axis are opposite to strains in the short axis, and when there is misalignment the two strain tensors detract from each other [5]. A recent study indicates that this problem might be less important [11]. Angle problems can be reduced by using the smallest possible sector and recording one wall at a time. Figure 2. Reconstructed three-dimensional color-coded strain rate images of the left ventricle from a subject with acute apical myocardial infarction Longitudinal shortening (contraction) is shown in yellow and lengthening in blue. Top: reconstructed bull’s eye views showing the whole ventricle at once, but with distorted area representation. Bottom: Three-dimensional surfaces seen from the antero-apical aspect. The left image is recorded in mid systole and the blue colored area represents positive strain rates, which means systolic lengthening, and is typical for infarcted myocardium. The right image is from early diastole and the yellow colored area, which represents negative strain rates indicates postsystolic shortening. Tissue Doppler imaging and coronary artery disease Smiseth et al. 423 An experimental study by Hashimoto et al. [12] suggests that assessment of strain rate in different myocardial lay- ers may be feasible. This application has obvious limita- tions with regard to lateral resolution, which is related to the high density of echo beams that is required. It re- mains to be determined if this approach can be used in a clinical setting. Tissue Doppler imaging-based indices of myocardial function Ejection phase indices Tissue Doppler imaging has excellent ability to quantify myocardial function and has good temporal resolution [1,13]. Ischemic regions are characterized by a decrease in peak systolic ejection velocity, and a decrease in peak early-diastolic myocardial lengthening velocity [14,15]. Measurement of peak ejection velocity is the most widely used TDI measure for quantifying regional func- tion in suspected coronary artery disease. Longitudinal velocity measurements are more reproducible than radial velocities, and are therefore usually preferred. On the other hand longitudinal velocities show more variability between segments and this complicates clinical use. Re- cently, reference values were presented from a group of normal individuals [16]. There is, however, need for larger age- and sex-stratified studies and these should include measurement of strain and strain rate as well. Several groups are currently working with establishing such reference values. A number of studies suggest that analysis of function during the isovolumic LV phases provide additional im- portant diagnostic information. In the subsequent para- graphs we will review some of the studies. Preejection indices Preejection velocity predicts recovery of function after reperfusion Experimental studies indicate that velocities during iso- volumic contraction (IVC) may serve as a means to de- termine degree of myocardial dysfunction during ische- mia [17]. In ventricles with preserved systolic function there is a dominantly positive longitudinal velocity dur- ing IVC, with only a minor negative velocity component. With progressive ischemia the positive velocity compo- nent diminishes, and the negative component increases. During severe ischemia the positive component is lost and replaced by a large negative IVC velocity (Fig. 3). The negative IVC velocity is a reflection of the early systolic lengthening, which is a hallmark of severe ische- mia. Penicka et al. [18] tested the ability of IVC velocities to predict recovery of myocardial function after coronary revascularization in myocardial infarction. They showed that a positive IVC velocity after revascularization pre- dicted recovery of function in the reperfused area. This study suggests that measurement of IVC velocities may provide important diagnostic information with regard to myocardial viability after coronary reperfusion. Does myocardial IVC acceleration reflect inotropy? Similar to LV ejection fraction, peak systolic ejection velocity is preload and afterload dependent. Vogel et al. [19] proposed that myocardial IVC acceleration (IVA) Figure 3. Data from an experimental study before (left panel) and during coronary artery occlusion (right panel) Before coronary occlusion there is a dominantly positive Doppler velocity spike during IVC and a more protracted velocity during ejection. During IVR there are only minor velocity spikes. During coronary occlusion the velocity profile is dominated by a large negative velocity during IVC and a marked positive velocity during IVR, while ejection velocities are near zero. The lower panels show regional function by sonomicrometry, and confirms that the negative IVC velocity during LAD occlusion represents systolic lengthening and the positive IVR velocity means postsystolic shortening. Modified from Edvardsen et al. [17]. 424 Imaging and echocardiography would be a load-independent measure of contractility. In an animal model they measured longitudinal myocardial velocities near the LV base, and demonstrated that IVA reflected myocardial contractility, and appeared to be load independent. However, this study was done in the nonischemic ventricle, and measurements were taken near the mitral ring, which means they measured in es- sence global LV function. In a recent experimental study Lyseggen et al. [20] validated IVA as a measure of re- gional function during myocardial ischemia. This study confirmed that IVA was related to global LV contractil- ity, but IVA did not reflect function in the ischemic myocardium. Thus, IVA appears to have limited poten- tial to serve as a measure of regional function during ischemia. Postejection indices It has been known for long that postsystolic shortening (LV long axis) and postsystolic thickening (short axis) are characteristic features of ischemic myocardium [21]. As alternative terminology one may use postejection shorten- ing and thickening, since the myocardium shortens and thickens after aortic valve closure. Postsystolic shorten- ing can be measured directly with strain Doppler echo- cardiography and is measured as myocardial shortening that occurs after cessation of aortic forward flow. Post- systolic shortening can also be imaged by velocity imag- ing, and is in the long axis represented by a positive velocity component during isovolumic relaxation (IVR). Figure 4 demonstrates postsystolic shortening as mea- sured by velocity imaging. As demonstrated by Voigt et al. [22] minor degrees of postsystolic shortening occurs in normal myocardium, and is not pathologic unless it exceeds a certain magni- tude in absolute terms or represents a substantial fraction (> 20%) of total myocardial shortening (Fig. 5). The mechanism of postsystolic shortening in normal myocar- dium is not defined, but may be related to the LV shape changes and untwisting motion that occur during IVR. Postsystolic shortening and viability in acute myocardial infarction Postsystolic shortening by DTI has been proposed as a marker of myocardial viability during acute coronary oc- clusion, with the rationale that it may represent active myocardial contraction. Postsystolic shortening, how- ever, may occur in entirely passive or necrotic myocar- dium as well as in actively contracting ischemic myocar- dium [23]. Therefore, the isolated finding of postsystolic shortening is nonspecific with regard to tissue viability. The mechanism of postsystolic shortening in passive myocardium is analogous to the behavior of a stretched elastic spring; it will recoil passively when the stretching force is removed. Thus, dyskinetic myocardium, which by definition is stretched in systole by nonischemic myo- cardium, will recoil during IVR when nonischemic myo- cardium relaxes and the stretching force drops abruptly. However, measurement of postsystolic shortening may help to identify viable myocardium, provided that strains during IVC and ejection are assessed simultaneously. First, if postsystolic shortening occurs in the absence of systolic lengthening passive recoil can be excluded, and therefore the postsystolic shortening represents delayed active contraction [23]. Second, as suggested by recent experimental data, when a segment is dyskinetic, but the Figure 4. Postsystolic shortening in ischemic myocardium Myocardial velocity curves from a patient with significant stenosis of the left anterior descending coronary artery. The dashed curve shows longitudinal velocity in a normal lateral segment. The continuous curve shows velocity in an ischemic segment in mid septum. This ischemic segment has reduced systolic velocity, and during early diastole there is a marked positive velocity (arrow), which represents postsystolic shortening. S, systolic velocity; E’, early-diastolic velocity; A’, late-diastolic velocity. Tissue Doppler imaging and coronary artery disease Smiseth et al. 425 postsystolic shortening far exceeds the systolic lengthen- ing in magnitude, it is likely that active contraction con- tributes to postsystolic shortening [24]. Thus, Skulstad et al. [24] proposed that the ratio between systolic length- ening and combined late systolic and postsystolic short- ening may serve as a marker of active as opposed to passive postsystolic shortening. The rationale for this as- sociation is that active wall tension will limit systolic lengthening and enhance active postsystolic shortening. A postsystolic strain index expressed as ratio between postsystolic shortening and systolic shortening has been proposed by Kukulski et al. [25•]. They showed that this index was a highly sensitive and specific marker of myo- cardial dysfunction during acute myocardial ischemia. Although this index may be useful since it “normalizes” the postsystolic shortening values, it has an evident limi- tation when studying segments with akinesia, and there- fore very small systolic strain. In the latter case even a postsystolic shortening of trivial magnitude may repre- sent a large fraction of systolic strain [26]. In these cases the absolute rather than the relative postsystolic short- ening will be of interest. Song et al. [27] investigated patients several months after myocardial infarction and found that postsystolic thick- ening as demonstrated by TDI was associated with signs of tissue viability. The study, however, was limited by absence of reference method or postintervention data that confirmed viability. From a clinical perspective the differentiation between active and passive postsystolic shortening is critical, since active contraction implies viable myocardium. Potentially, assessment of postsystolic shortening may help in patient triage in acute myocardial infarction, in particular when thrombolysis has been primary treat- ment and transfer for rescue PCI is considered. At the present time, however, we lack prospective trials that confirm the clinical value of assessing postsystolic short- ening in acute myocardial infarction. Postsystolic shortening in stress echocardiography In the setting of stress echocardiography, when postsys- tolic shortening is absent during baseline, but appears during dobutamine it is a marker of myocardial ischemia [28•] (Fig. 6). Furthermore, as demonstrated in an experimental study by Weidemann et al. [26] dobutamine-induced enhance- ment of postsystolic thickening along with a reduction of systolic thickening differentiates nontransmural from transmural chronic infarctions. Therefore, measurement of postsystolic shortening/thickening is a promising ap- proach in the analysis of stress-echocardiography record- ings. Stress echocardiography Conventional stress echocardiography is based on visual assessment of systolic wall thickening and endocardial excursion, and suffers from being subjective and pro- vides only qualitative or semiquantitative data [29]. Fur- thermore, visual assessment has poor temporal resolu- tion, and therefore has limited ability to detect more subtle changes in myocardial function [30,31]. Tissue Doppler represents a means to quantify regional function objectively and with much better temporal resolution [32,33]. Pulsed Doppler is too time consuming to allow measurements from all segments during the final stress Figure 5. Postsystolic shortening in a normal individual Recordings from the midseptal region in a young control subject, showing strain rate (a) and strain (b). ECG is included for referencing. The timings of mitral valve closure (MVC), aortic valve opening (AVO), aortic valve closure (AVC), and mitral valve opening (MVO) are indicated. In this person there is slight postsystolic shortening that starts at the time of mitral valve opening, as indicated by negative strain rate and a decrease in strain. Reproduced from Voigt et al. [22]. 426 Imaging and echocardiography stage, while color Doppler recordings are obtained much faster and measurements are done during post processing [34]. Fraser et al. [35•] in the MYDISE (MYocardial Doppler In Stress Echocardiography) study have examined the feasibility and reproducibility of segmental tissue Dopp- ler in dobutamine stress echocardiography. They re- ported that analysis was feasible in 90% of examined segments in 92 normal subjects, but their analysis was limited to basal and mid wall segments. Reproducibility was examined in the same cine-loops from 10 subjects. Coefficients of variation for peak systolic velocity and time to peak velocity were up to 18% in basal segments and 28% in midwall segments at peak stress. The clinical utility of the method then depends on the magnitude of the increase from baseline to peak stress. The same group addressed the diagnostic accuracy of tissue Doppler in stress echo in a population of 289 sub- jects by Mädler et al. [36•]. Peak systolic velocity at peak stress, rather than change in velocity from baseline was the best discriminator of disease, but sensitivity was only 63 to 69% and specificity 60 to 67% for the different vascular regions, which are somewhat lower values than previously reported by the Brisbane group [37]. How- ever, when Mädler et al. [36] applied a regression model, which included age, gender, and peak heart rate, sensi- tivity increased to 80 to 93% and specificity to 80 to 82%. These results imply that not only heart rate, but also age and gender should be taken into account when interpret- ing stress echo by tissue Doppler. Importantly, the Bris- bane group has shown that less-experienced observers obtain a significant improvement in sensitivity and ac- curacy using TDI relative to visual assessment in inter- preting dobutamine echocardiography [38]. A few studies using strain rate imaging in stress echocar- diography have been recently published. Davidavicius et al. [39] found that 95% of segments could be analyzed Figure 6. Strain and strain rate responses during stress echo This figure displays LV two-chamber perfusion scintigraphic images and color-coded strain rate images (a), and strain rate (b), strain (c), and ECG (d) traces prior to and at peak dobutamine stress. The arrow in the upper right panel points to a perfusion defect. Strain and strain rates are recorded from the ischemic region and a nonischemic region. During peak stress the strain trace from the ischemic apical region demonstrates early-systolic lengthening and postsystolic shortening. SR peak sys indicate peak systolic strain. T bos and t eos indicate beginning and end of shortening, respectively. E max ,E et , and E ps indicate max strain during the heart cycle, strain during ejection and postsystolic strains, respectively. Reproduced from Voigt et al. [28]. Tissue Doppler imaging and coronary artery disease Smiseth et al. 427 during dobutamine stress. Due to noise problems strain rate imaging was not feasible during treadmill or bicycle stress. The study, however, was small and was limited to healthy individuals. Kowalski et al. [40] extended the testing of SRI to patients with coronary artery disease. The normal response during dobutamine stress was an increase in strain rate and strain at low dose dobutamine, a further increase in strain rate at high dose, when strain showed a plateau due to the increased heart rate. Their study confirms that SRI may have a clinical potential, but was not designed to determine the ability of SRI to di- agnose coronary artery disease. The clinical value of SRI was addressed by Voigt et al. [28]. The study included 44 patients and single photon emission computed tomography (SPECT) was used as reference method for ischemia. The ratio of postsystolic shortening to maximum segmental shortening was the best parameter to identify stress-induced ischemia. Fur- thermore, compared with conventional gray scale readings SRI curved M-mode improved sensitivity/specificity from 81/82% to 86/89%. The statistical significance of this difference, however, is not given in the paper. Abra- ham et al. [41] introduced the time to onset of regional LV relaxation as a measure of ischemia during stress echo. This is an interesting approach that needs further clinical testing. Conclusion Tissue Doppler echocardiography has proved to be an accurate method for quantitative evaluation of regional myocardial function, and the most widely used measure in coronary disease is peak velocity during LV ejection. So far TDI has not replaced conventional grey-scale im- aging in the assessment of regional LV function. Further studies are needed to determine if inclusion of pre- injection and post-ejection velocities and timing of events may increase the diagnostic power. Recent devel- opments in 3-D cardiac imaging could allow more com- prehensive visualization of myocardial function. Ulti- mately, for the clinician it is critical that the advantages of the new quantitative methodologies outweigh their disadvantages in terms of complexity and cost. 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