Doppler echocardiography and myocardial dyssynchrony a practical update of old and new ultrasound technologies
Morbidity and mortality rates are higher in patients withsevere left ventricular (LV) systolic dysfunction and ECGderived prolonged QRS interval than in those with normal QRS duration .Bi-Ventricular Pacing(BIVP) andCardiac Resynchronization Therapy(CRT) have becomeadditional treatment aimed to synchronizing biventricular activation and contraction in patients with severechronic heart failure (CHF) associated with interventricular conduction delay. CRT is effective in improving functional capacity and degree of secondary mitralregurgitation [2-4] and, above all, in reducing the mortality in cases of refractory CHF. NYHA classes III-IV, a LVejection fraction (EF) of≤35%, a LV end-diastolic diame ter > 30 mm/m2and a surface ECG derived QRS duration> 120 ms, together with a need for maximal pharmacological therapy, are considered from guidelines to selectpatients for CRT .QRS duration is currently used on the grounds that itreflects the presence of ventricular dyssynchrony. However, 30–40% of patients selected on the basis of a prolonged QRS do not receive benefit by CRT since they donot show any significant inverse LV remodeling (a≥15%reduction of LV end-systolic volume six months afterdevice implantation) [6,7]. Furthermore, QRS durationdoes not accurately distinguish responders to CRT .Although factors responsible for the absence of favourableresponse may be lead dislodgement or inappropriate location of LV lead, mechanical dyssynchrony (particularlyintra-ventricular dyssynchrony) seems to be much moreimportant than electrical dyssinchrony, and Dopplerechocardiography should be widely used before and afterimplantation of a CRT device [9,10].
Pre- and post-echocardiographic assessment includes conventional and/or specific applications ranging from Mmode and pulsed/continuous Doppler, to pulsed TissueDoppler, the off-line analysis of colour Tissue Doppler,Strain Rate Imaging (SRI), and real time 3-D reconstruction [9-13]. The different modalities of the transthoracicultrasound approach are able to identify the 3 differentkinds of mechanical dyssynchrony: 1. Atrio-ventriculardyssinchrony, 2. Inter-ventricular dyssynchrony, 3. Intraventricular dyssynchrony.
1. Atrio-ventricular dyssynchrony
Atrio-ventricular (AV) dyssynchrony occurs in patientswith dilated cardiomyopathy and first degree AV blockand was the first objective of CRT by bicameral pacemakers in the early 1990s . AV dyssynchrony reduces theduration of ventricular filling, thus inducing the appearance of diastolic mitral and tricuspid regurgitation andreducing stroke volume. The optimal AV delay after CRTis short, but a longer delay may be necessary in some cases(e.g., in the presence of concomitant inter-atrial delay).Optimizing AV delay is guided by a Doppler recording oftransmitral inflow (Mitral inflow method) [11-13,15]which requires recording the mitral inflow pattern at asweep speed of 100 mm/s, with the sample volume placedat the tips of the mitral leaflets; mitral valve closure mustbe clearly defined at the time of ECG R wave (Figure 1).The method cannot be applied in the presence of atrialfibrillation (no A velocity). Furthermore, when the AVdelay is short (= 60–80 ms), the duration of A velocitymay become shorter inducing less atrial contribution buttotal LV filling time increases.
2. Inter-ventricular dyssynchrony
Inter-ventricular dyssynchrony represents the discordancebetween the times of right ventricular (RV) and LV contraction. PW or CW Doppler images of aortic and pulmonary flow velocities are currently used to measure theinter-ventricular mechanical delay (IVMD), whichincludes recording of LV outflow tract (apical 5-chamberview) and RV outflow tract (parasternal short-axis view ofthe great vessels) and calculating the difference in timebetween ECG-derived Q wave onset and the onset of LVoutflow and the time between the onset of Q and theonset of RV outflow [11,12] (Figure 2). These time intervals respectively reflect LV and RV pre-ejection period(PEP). IVMD values of > 40 ms and values of LV PEP of >140 ms are considered pathological . Doppler recording of LV and RV outflow velocities (sweep speed of 100mm/s) requires appropriate gain and wall filter settings tovisualize the opening and closing clicks. When using PWDoppler, the sample volume has to be placed proximallyto the pulmonary and the aortic valve. The limitation ofthis method include the presence of pulmonary arterialhypertension and/or RV systolic dysfunction, which canprolong RV PEP, and a concomitantly impaired increaseof LV pressure in very severe CHF.
Alternatively, pulsed Tissue Doppler can be used to determine IVMD by measuring the time from QRS onset to thepeak myocardial systolic velocities (Sm) of the RV free wall(tricuspid annulus) versus the same time of LV lateralmitral annulus (apical 4-chamber view) .
It is important to state that intraventricular dyssynchronydoes not correlate with reverse LV remodeling after CRT,even when data from patients with and without coronaryartery disease are evaluated separately [17-19].
3. Intra-ventricular mechanical dyssynchrony
Intra-ventricular dyssynchrony is characterized by eitherpremature or late contraction of LV wall segments due todelayed electrical conduction . It can be identified bymeans of simple M-mode, pulsed Tissue Doppler, or, better, by colour Tissue Velocity Imaging (TVI), SRI and 3-Dechocardiography.
Intra-ventricular mechanical delay can be determined onthe basis of the simple M-mode-derivedseptal-to-posteriorwall motion delay(SPWMD), i.e., the difference in timingof septal and posterior wall contraction [12,21,22]. TheM-mode cursor is positioned perpendicular to the septumand 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-derivedQ wave to the initial peak posterior displacement of theseptum, and the time from the onset of QRS to the peaksystolic displacement of posterior wall (sweep speed of100 mm/s) (Figure 3). In the original experience of Pitzalis et al on 20 patients with advanced heart failure, aSPWMD (determined in parasternal short-axis view) of >130 ms was considered pathological and SPWMD predicted inverse LV remodeling and long-term clinicalimprovement after CRT, with 100% sensitivity, 63% specificity and 85% accuracy [21,22].
The main advantages ofthis method correspond to the low-cost technique and theavailability in all the echocardiographic machines. Thelimitations include the impossibility to measure SPWMDin patients with a poor acoustic window, previous septalor posterior wall myocardial infarction, or abnormal septal motion secondary to RV pressure or volume overload.In addition, M-mode can only visualize dyssinchrony ofthe anterior septum or posterior wall whereas other LVwalls can be involved. Marcus et al have underlined thelow feasibility of SPWMD (measured in parasternal longaxis view), which had also poor sensitivity (24%) and speume in a specific myocardial segment and to measure Qto peak Smand/or Q to Smonset in various LV segments.The number of LV segments to be evaluated includemainly a 12-segment model (LV basal and middle segments in 4-, 2- and 5-chamber views) whereas LV apicalsegments are not considered reliable because of the basalapical myocardial gradient own of Tissue Doppler. Technical refinements include the need to set the velocity scaleof PW Tissue Doppler to display spectral velocities of 20cm/s above and below the zero baseline because myocardial motion is characterized by low velocities. SpectralDoppler gain must be usually reduced, wall filtersadjusted and spectral velocities recorded at sweep speed of100 mm/s (during held respiratory expiration), in orderto obtain the clearest delineation of Smonset and peak.Electromechanical delay has to be averaged over at least 3cardiac cycles. The main limitation of PW Tissue Dopplercorresponds to the impossibility of measuring the timeintervals of different segments during the same cardiaccycle. It is also necessary to take into account that the Smrecorded in apical views reflects LV longitudinal shortening and not circumferential contraction.
Colour Tissue Doppler
Off-line colour Tissue Doppler derived Tissue VelocityImaging (TVI), Tissue Synchronization Imaging (TSI) andSRI can be used to assess intra-ventricular dyssynchrony inthe longitudinal plane (apical views). The commonadvantages of these techniques is the possibility of measuring the dyssynchrony of opposite LV walls (= horizontaldyssynchrony) and of different segments of the same LVwall (= vertical dyssynchrony) in a given view, from thesame cardiac cycle (Figure 6). Like to PW Tissue Doppler,TVI measures thetime to Smpeak(Ts) or thetime to Smonsetin LV basal and middle segments of the three standard apical views [27,28] (Figure 7). By identifying thepresence of one or more differences > 50 ms amongregional times of Smonset, Ghio and coworkers have demonstrated that intraventricular dyssynchrony is detectableeven in 29.5 % of patients with advanced LV dysfunctionbut normal QRS duration . Using a LV 12-segmentmodel (TVI apical measurements are also unreliable), adyssynchrony index(DI) can be derived as the standarddeviation of the average values of Ts(Ts-SD) [27,30] (Figure 8). In his personal experience Yu et al have found that a Ts-SD of > 32.6 ms predicts inverse LV remodeling afterCRT with 100% sensitivity, 100% specificity and 100%accuracy in 30 candidates to CRT  (Figure 8).
TSI is an implementation of Ts method. It displays Ts inmultiple LV segments by colour coding wall motion green(corresponding to early systolic contraction) or red, whichcorresponds to delayed contraction (sensitivity = 87%,specificity = 81% and accuracy = 84% at a cut-off value of34.4 ms in 56 patients with severe heart failure) .
Ultrasound instrumentations running Colour Tissue Doppler are also able to determine regional electromechanicaldelay by means of off-line analysis of longitudinal SRIwhich, in comparison to TVI, has the advantage of distinguishing active contraction from passive myocardialmotion. In general, the detection of intra-ventricular dyssynchrony by means of the strain (%) and strain rate (1/sec) is based on unmasking myocardial "post-systolicshortening"after aortic valve closure (AVC), i.e. during thediastolic myocardial relaxation time (Figure 9). Variousmethods have been proposed for calculating intra-ventricular dyssynchrony by SRI, some of which (e.g., % of LVbase with delayed contraction) predict accurately LVinverse remodeling after CRT but are complicate andrequires considerable experience of the operator .One simple method, from Mele and coworkers, measuresthestandard deviation of the averaged time-to-peak-strain(TPS-SD, ms) of 12 LV basal and mid-segments obtainedfrom the three standard apical views: a TP-SD of > 60 msis associated with a good response to CRT in 37 patientswith dilated cardiomyopathy, although sensitivity, specificity and accuracy have not been determined by thismethod  (Figure 10). Another recent possibility, proposed by Porciani et al, considers the time spent by 12 LVsegments in contracting after AVC, i.e., during the isovolumic relaxation time, and measures thesum of the time ofstrain tracing exceeding AVC(ExcT)on the 12 LV basaland mid-segments (cut-off value = 760 ms, 93.5% sensitivity and 82.8% specificity) (Figure 11) . Thismethod had the advantage to distinguish "contractilesystolic asynchrony", i.e., temporal dispersion of theregional electromechanical delay within the ejectivephase, from "diastolic contractile asynchrony", whichcannot be detected by analysing the ejection phase of thecardiac cycle alone. Of note, in their experience, Porcianiet al have found good sensitivity (= 82%) but poor specificity (= 39%) of TVI-derived Ts-SD. Although Yu et al demonstrated that SRI-derived post-systolic shortening of 12LV segments is a good predictor of inverse LV remodelingonly for the non-ischemic patients , SRI indexes havethe conceptual advantages to refer to "true" contractionphenomena 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 Dopplerderived techniques require high 2-D frames rates (>90frames/s)  and that 2-D image should be optimizedwith a narrow sector width that includes the basal andmiddle segments of opposite LV walls and depth settingthat include left ventricle, mitral annulus and the base ofthe left atrium . Colour Tissue Doppler gain has to beadjusted in order to display myocardial motion clearly. Atleast 3 cardiac cycles should be recorded during held respiration. Before performing measurements, aortic valveopening (= AVO) and AVC must be marked by means ofa previous recorded PW Doppler of LV outflow tract, inorder to avoid confusion between systolic (normal) andpost-systolic (abnormal) contraction .The 2-D strain (speckle tracking) technique has veryrecently been used to assess radial dyssynchrony before/after CRT. Speckle tracking has been applied to routinemid-ventricular short-axis images to calculate radial strainfrom multiple circumferential points averaged to sixstandard segments and dyssynchrony from timing of peakradial strain has been demonstrated to be correlated withTissue Doppler measures in 47 subjects . Atime difference≥130 ms between the radial strain peak of LV posteriorwall and anterior septumhas shown to be highly predictive of an improved EF during follow-up, with 89% sensitivity and 83% specificity .
Three-dimensional (3-D) echocardiography allows intraventricular dyssynchrony to be evaluated by analyzing LVwall motion in multiple apical planes during the samecardiac cycle. It also offers better spatial resolution than asingle plane. The global LV volumetric dataset has beenused to determine a dyssynchrony index that correspondsto the standard deviation of the average of the time inter
vals needed by multiple LV segments to reach minimalend-systolic volume  (Figure 12). This index isexpressed as the percent value of the overall cardiac cycle,in order to be able to compare patients with differentheart rates. CRT responders (= an improvement of NHYAclass) show a significant reduction of this 3-D dyssynchrony index, which parallels the reduction of LV enddiastolic volume and the increase in EF . The agreement between 3-D and TVI in identifying the magnitudeof intra-ventricular dyssynchrony and the site of maximaldelay is poor at only 16% . Advantages of the 3-Dmethod include the possibility of evaluating all LV segments and all of the radial, longitudinal, circumferentialelements of LV contraction. The limitations of 3-Dmethod 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 inthe 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 standardapical views during the same heart beating (Triplane). Theimages can also be acquired in TSI modality (Figure 13),thus allowing 3-D "surface rendering" visualization of theextent 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 etal [41,42] have pointed out the feasibility and the rapidityof acquisition by using this tool.
A very recent study hasdemonstrated that atriplane Ts-SD(i.e., the standard deviation of time delays in all LV segments calculated by 3-DTSI) = 35.8 ms predicts an acute (48 hours after CRT)reverse LV remodeling with 91% sensitivity and 85% specificity .
What to measure before and after CRT
On the grounds of the multiple mentioned experiences,the ultrasound examination of candidates for CRTrequires specific measurements of mechanical dyssynchrony. This can be made by combining PW/CW Dopplerand M-mode echocardiography (or PW Tissue Doppler orcolor Tissue Doppler derived techniques or 3-D imaging).Table 1 lists the cut-off values of the main techniques thatpredict responders to CRT while Table 2 sumarizes sensitivity, specificity and accuracy, and also confirmatory orcontroversial data of these techniques. While confirmatory results are shown only by the same researchers whohad created the single methods, subsequent studies byother authors have reported conflicting results when usingprevious validated indexes. It has also to be taken intoaccount that all the proposed methods and techniqueshave been applied on restricted population sample sizeand information about the time needed for data acquisition and/or analysis has been rarely reported. In general,intra-ventricular dyssynchrony appears more predictive ofCRT response than inter-ventricular dyssynchrony and theglobal amount of LV dyssynchrony seems to be critical byusing different ultrasound techniques: the greater intraventricular dyssynchrony, the higher the possibility of significant inverse LV remodeling. When compared to othertechniques, 3-D echocardiography has the potential,important advantage to identify the global cardiac dyssynchrony during the same heart beating. After CRT, Dopplerechocardiography provides the possibility to evaluate theoptimal AV delay and V-V delay setting that maximizes LVsystolic function.
Although several studies have demonstrated the superiority of ultrasound over QRS duration to assess LV dyssynchrony, there are no conclusive data on prediction of CRT response either using conventional or more advancedechocardiographic technologies. The Cardiac Resynchronization-Heart Failure (CARE-HF) study is the only largerandomized and controlled trial that required direct,ultrasound measurement of cardiac dyssynchrony in asubset of patients with mild to moderate QRS enlargement (= 120–149 ms) (5). However, in the CARE-HFstudy only 92 patients (11%) underwent CRT based onDoppler echocardiographic indexes of myocardial dyssynchrony. Of consequence, the results cannot be consideredexhaustive. It is not unexpected, therefore, that the ECGrepresentation of abnormal cardiac conduction stillremains as the main criterion to identify patients with dyssynchronous ventricular contraction. Accordingly, noconsensus definition of cardiac dyssynchrony exists as yetfrom the main cardiologic associations [44-47], althoughseveral of the mentioned echocardiographic measuresappear very promising.