Intra-ventricular mechanical delay can be determined on the basis of the simple M-mode-derived septal-to-posterior wall motion delay (SPWMD), i.e., the difference in timing of septal and posterior wall contraction 122122. The M-mode cursor is positioned perpendicular to the septum and posterior wall at the base of the left ventricle, in parasternal short-axis (or long-axis) view: SPWMD is the difference between the time from the onset of ECG-derived Q wave to the initial peak posterior displacement of the septum, and the time from the onset of QRS to the peak systolic displacement of posterior wall (sweep speed of 100 mm/s) (Figure 3). In the original experience of Pitzalis et al on 20 patients with advanced heart failure, a SPWMD (determined in parasternal short-axis view) of > 130 ms was considered pathological and SPWMD predicted inverse LV remodeling and long-term clinical improvement after CRT, with 100% sensitivity, 63% specificity and 85% accuracy 2122. The main advantages of this method correspond to the low-cost technique and the availability in all the echocardiographic machines. The limitations include the impossibility to measure SPWMD in patients with a poor acoustic window, previous septal or posterior wall myocardial infarction, or abnormal septal motion secondary to RV pressure or volume overload. In addition, M-mode can only visualize dyssinchrony of the anterior septum or posterior wall whereas other LV walls can be involved. Marcus et al have underlined the low feasibility of SPWMD (measured in parasternal long-axis view), which had also poor sensitivity (24%) and specificity (66%) in predicting the response to CRT of 79 heart failure patients 23.

A very recent method, reported by Sassone et al 24, determines lateral wall post-systolic displacement (LWPSD), measured as the difference of intervals from QRS onset to maximal systolic displacement of the basal LV lateral wall (assessed by M-mode in the apical 4-chamber view) and from QRS onset to the beginning of transmitral E velocity (assessed by pulsed Doppler of mitral inflow) (Figure 4). A positive LWPSD, i.e. a longer interval to maximal inward displacement of LV lateral wall than the interval to opening of the mitral valve, identifies a severe post-systolic contraction and has been demonstrated to be an independent predictor of CRT response in 48 patients with end-stage heart failure and left bundle branch block. Of interest, despite evaluating intra-ventricular dissynchrony based on delay of a single myocardial wall, LWPSD could predict CRT response. This may rely to the fact that, in the presence of left bundle branch block, the lateral wall is the latest to be activated, theoretically representing the optimal target for LV lead positioning. This method has not yet tested in patients without left bundle branch block and its diagnostic accuracy is unknown. In addition. it needs the identical heart rate when measuring the M-mode and pulse Doppler imaging.

Determining the time of myocardial systolic velocities (S_m) is an important and easy echocardiographic means of assessing CHF before/after CRT. The advantage of PW Tissue Doppler is its excellent temporal resolution for measuring intraventricular mechanical dyssinchrony, and its availability in the majority of cardiac ultrasound systems. Various PW Tissue Doppler parameters have been proposed 25. The most widely used measurements correspond to the time interval between the onset of ECG-derived QRS and the S_m peak (= time to S_m peak) and the time interval between the onset of QRS and the onset of S_m (= time to S_m onset), which correspond to LV PEP (Figure 5). Intra-ventricular mechanical delay has been defined for differences of > 65 ms of time to S_m peak between LV segments 26. Receiver-operator characteristic curve analysis demonstrated that this cut-off value yielded a sensitivity and specificity of 80% to predict clinical improvement and of 92% to predict LV reverse remodeling in 85 patients with end-stage heart failure, QRS duration > 120 ms, and left bundle-branch block 26.

Extensions of these method have been proposed by recording 2D imaging in the 4- 2- and 5-chamber apical views, in order to place PW Tissue Doppler sample volume in a specific myocardial segment and to measure Q to peak S_m and/or Q to S_m onset in various LV segments. The number of LV segments to be evaluated include mainly a 12-segment model (LV basal and middle segments in 4-, 2- and 5-chamber views) whereas LV apical segments are not considered reliable because of the basal-apical myocardial gradient own of Tissue Doppler. Technical refinements include the need to set the velocity scale of PW Tissue Doppler to display spectral velocities of 20 cm/s above and below the zero baseline because myocardial motion is characterized by low velocities. Spectral Doppler gain must be usually reduced, wall filters adjusted and spectral velocities recorded at sweep speed of 100 mm/s (during held respiratory expiration), in order to obtain the clearest delineation of S_m onset and peak. Electromechanical delay has to be averaged over at least 3 cardiac cycles. The main limitation of PW Tissue Doppler corresponds to the impossibility of measuring the time intervals of different segments during the same cardiac cycle. It is also necessary to take into account that the S_m recorded in apical views reflects LV longitudinal shortening and not circumferential contraction.

Off-line colour Tissue Doppler derived Tissue Velocity Imaging (TVI), Tissue Synchronization Imaging (TSI) and SRI can be used to assess intra-ventricular dyssynchrony in the longitudinal plane (apical views). The common advantages of these techniques is the possibility of measuring the dyssynchrony of opposite LV walls (= horizontal dyssynchrony) and of different segments of the same LV wall (= vertical dyssynchrony) in a given view, from the same cardiac cycle (Figure 6). Like to PW Tissue Doppler, TVI measures the time to S_m peak (T_s) or the time to S_m onset in LV basal and middle segments of the three standard apical views 2728 (Figure 7). By identifying the presence of one or more differences > 50 ms among regional times of S_m onset, Ghio and coworkers have demonstrated that intraventricular dyssynchrony is detectable even in 29.5 % of patients with advanced LV dysfunction but normal QRS duration 29. Using a LV 12-segment model (TVI apical measurements are also unreliable), a dyssynchrony index (DI) can be derived as the standard deviation of the average values of T_s (T_s-SD) 2730 (Figure 8). In his personal experience Yu et al have found that a T_s-SD of > 32.6 ms predicts inverse LV remodeling after CRT with 100% sensitivity, 100% specificity and 100% accuracy in 30 candidates to CRT 30 (Figure 8).

TSI is an implementation of T_s method. It displays T_s in multiple LV segments by colour coding wall motion green (corresponding to early systolic contraction) or red, which corresponds to delayed contraction (sensitivity = 87%, specificity = 81% and accuracy = 84% at a cut-off value of 34.4 ms in 56 patients with severe heart failure) 31.

Ultrasound instrumentations running Colour Tissue Doppler are also able to determine regional electromechanical delay by means of off-line analysis of longitudinal SRI which, in comparison to TVI, has the advantage of distinguishing active contraction from passive myocardial motion. In general, the detection of intra-ventricular dyssynchrony by means of the strain (%) and strain rate (1/sec) is based on unmasking myocardial "post-systolic shortening" after aortic valve closure (AVC), i.e. during the diastolic myocardial relaxation time (Figure 9). Various methods have been proposed for calculating intra-ventricular dyssynchrony by SRI, some of which (e.g., % of LV base with delayed contraction) predict accurately LV inverse remodeling after CRT but are complicate and requires considerable experience of the operator 32. One simple method, from Mele and coworkers, measures the standard deviation of the averaged time-to-peak-strain (TPS-SD, ms) of 12 LV basal and mid-segments obtained from the three standard apical views: a TP-SD of > 60 ms is associated with a good response to CRT in 37 patients with dilated cardiomyopathy, although sensitivity, specificity and accuracy have not been determined by this method 33 (Figure 10). Another recent possibility, proposed by Porciani et al, considers the time spent by 12 LV segments in contracting after AVC, i.e., during the isovolumic relaxation time, and measures the sum of the time of strain tracing exceeding AVC (ExcT) on the 12 LV basal and mid-segments (cut-off value = 760 ms, 93.5% sensitivity and 82.8% specificity) (Figure 11) 34. This method had the advantage to distinguish "contractile systolic asynchrony", i.e., temporal dispersion of the regional electromechanical delay within the ejective phase, from "diastolic contractile asynchrony", which cannot be detected by analysing the ejection phase of the cardiac cycle alone. Of note, in their experience, Porciani et al have found good sensitivity (= 82%) but poor specificity (= 39%) of TVI-derived T_s-SD. Although Yu et al demonstrated that SRI-derived post-systolic shortening of 12 LV segments is a good predictor of inverse LV remodeling only for the non-ischemic patients 35, SRI indexes have the conceptual advantages to refer to "true" contraction phenomena while colour TVI is not able to distinguish "active" and "passive" motion of LV segments.

It is important to point out that all colour Tissue Doppler derived techniques require high 2-D frames rates (>90 frames/s) 36 and that 2-D image should be optimized with a narrow sector width that includes the basal and middle segments of opposite LV walls and depth setting that include left ventricle, mitral annulus and the base of the left atrium 37. Colour Tissue Doppler gain has to be adjusted in order to display myocardial motion clearly. At least 3 cardiac cycles should be recorded during held respiration. Before performing measurements, aortic valve opening (= AVO) and AVC must be marked by means of a previous recorded PW Doppler of LV outflow tract, in order to avoid confusion between systolic (normal) and post-systolic (abnormal) contraction 37.

The 2-D strain (speckle tracking) technique has very recently been used to assess radial dyssynchrony before/after CRT. Speckle tracking has been applied to routine mid-ventricular short-axis images to calculate radial strain from multiple circumferential points averaged to six standard segments and dyssynchrony from timing of peak radial strain has been demonstrated to be correlated with Tissue Doppler measures in 47 subjects 38. A time difference ≥ 130 ms between the radial strain peak of LV posterior wall and anterior septum has shown to be highly predictive of an improved EF during follow-up, with 89% sensitivity and 83% specificity 38.

Three-dimensional (3-D) echocardiography allows intra-ventricular dyssynchrony to be evaluated by analyzing LV wall motion in multiple apical planes during the same cardiac cycle. It also offers better spatial resolution than a single plane. The global LV volumetric dataset has been used to determine a dyssynchrony index that corresponds to the standard deviation of the average of the time intervals needed by multiple LV segments to reach minimal end-systolic volume 39 (Figure 12). This index is expressed as the percent value of the overall cardiac cycle, in order to be able to compare patients with different heart rates. CRT responders (= an improvement of NHYA class) show a significant reduction of this 3-D dyssynchrony index, which parallels the reduction of LV end-diastolic volume and the increase in EF 40. The agreement between 3-D and TVI in identifying the magnitude of intra-ventricular dyssynchrony and the site of maximal delay is poor at only 16% 39. Advantages of the 3-D method include the possibility of evaluating all LV segments and all of the radial, longitudinal, circumferential elements of LV contraction. The limitations of 3-D method are its suboptimal feasibility (<80%), its temporal resolution of about 40–50 ms, and its inability to distinguish active from passive motion or to make analysis in the presence of atrial fibrillation and/or recurrent premature beats. Furthermore, the index does not yet have a recognized cut-off point.

A new "real-time" 3D approach acquires three standard apical views during the same heart beating (Triplane). The images can also be acquired in TSI modality (Figure 13), thus allowing 3-D "surface rendering" visualization of the extent of dyssynchrony. The method is fast (a few seconds) and easy to perform, but has a lower temporal resolution than 2-D TSI. Partial experiences from Badano et al 4142 have pointed out the feasibility and the rapidity of acquisition by using this tool. A very recent study has demonstrated that a triplane T_s-SD (i.e., the standard deviation of time delays in all LV segments calculated by 3-D TSI) = 35.8 ms predicts an acute (48 hours after CRT) reverse LV remodeling with 91% sensitivity and 85% specificity 43.