Is mechanical dyssynchrony still a major determinant for responses after cardiac resynchronization therapy?

Journal of Cardiology (2011) 57, 239—248

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/jjcc

Review

Is mechanical dyssynchrony still a major determinant for responses after cardiac resynchronization therapy? Qing Zhang (MD, PhD) a,b, Cheuk Man Yu (MD) b,∗ a

Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong

b

Received 10 February 2011; accepted 10 February 2011

KEYWORDS Cardiac resynchronization therapy; Mechanical dyssynchrony; Cardiac imaging; Response; Predictor

Summary The assessment of mechanical dyssynchrony by advanced echocardiographic technologies and its importance in selecting more appropriate candidates for cardiac resynchronization therapy (CRT) have been disputed, after the announcement of the Predictors of Response to CRT (PROSPECT) trial, as the first evidence derived from a multicenter study. However, attempts in this field have never been stopped, as it appears that the fundamental mechanism of CRT is the correction of dyssynchrony where the detection of baseline dyssynchrony is of particular significance. The QRS width provides simple but very limited information. On the other hand, non-invasive imaging tools such as echocardiography have the capacity for more detailed analysis of mechanical dyssynchrony. We reviewed a number of clinical studies published in the post-PROSPECT era, designed to figure out a predictive algorithm where dyssynchrony measure is included, for identifying the most suitable patients before device implantation. From the analysis, mechanical dyssynchrony remains to be a major determinant for clinical outcomes after CRT, although discrepancies have arisen with respect to the singlecenter nature, echocardiographic methodologies, and relative merit when compared with other predicting factors. © 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Contents Introduction.............................................................................................................. Learning lessons from the PROSPECT trial ................................................................................ New evidence for mechanical dyssynchrony in CRT .......................................................................

∗ Corresponding author at: Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital & Institute of Vascular Medicine, The Chinese University of Hong Kong, Sha Tin, NT, Hong Kong. Tel.: +852 2632 3127; fax: +852 2637 5643. E-mail address: [email protected] (C.M. Yu).

0914-5087/$ — see front matter © 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jjcc.2011.02.004

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240

Q. Zhang, C.M. Yu Mechanical dyssynchrony at rest by echocardiography............................................................... Mechanical dyssynchrony during stress echocardiography............................................................ Mechanical dyssynchrony by other imaging modalities ............................................................... Conclusion ............................................................................................................. References .............................................................................................................

Introduction Cardiac resynchronization therapy (CRT) is one of the most rapidly evolving fields in heart failure management over the last decade [1]. There has been compelling evidence from multicenter clinical trials that CRT not only improves symptoms and cardiac function, but also reduces heart failure hospitalization and cardiovascular mortality in patients with advanced heart failure. However, it remains to be a major issue that based on the current guidelines for patient selection, non-responders to the therapy are constantly observed in about 30—40% of patients receiving CRT [2,3]. As the correction of left ventricular (LV) mechanical dyssynchrony has been suggested to be one of the major mechanisms for CRT, its detection should be of clinical importance in estimating the probability of response to the therapy. Not surprisingly, lack of mechanical dyssynchrony assessed by noninvasive echocardiographic techniques is found to be closely correlated to non-response in numerous single-center clinical trials, while other factors also attributable are extensive myocardial scar at the posterolateral wall or even the whole LV, lack of adequate contractile reserve, high pulmonary pressure, severe mitral regurgitation, non-posterolateral LV lead position, and suboptimal atrioventricular or interventricular delay programming [2,4,5]. Nevertheless, the results of the Predictors of Response to CRT (PROSPECT) trial, the first multicenter trial, indicated that no single echocardiographic measure of mechanical dyssynchrony could predict CRT responses with a good sensitivity and specificity, and therefore it is not recommended to improve patient selection beyond the current criteria of QRS durations [6]. Since then, researchers continue to quest for potential dyssynchronyrelated parameters which may predict a positive outcome in CRT population. The current review will provide a comprehensive description of the role of dyssynchrony in the post-PROSPECT era.

Learning lessons from the PROSPECT trial The PROSPECT trial was a multicenter, prospective, non-randomized study designed to evaluate selected echocardiographic indices of mechanical dyssynchrony for their capability in predicting responses to CRT. There were 12 parameters tested for a clinical composite score and LV end-systolic volume (LVESV) at 6 months as the primary outcomes, which being useful in previous single-center studies. Echocardiographic parameters were measured by conventional M-mode, Doppler echocardiography to advanced tissue Doppler imaging (TDI). The study reported a large variability in the analysis of mechanical dyssynchrony by echocardiography (up to

241 243 245 245 245

70% when using M-mode method) and a low area under the curve (AUC) in the prediction of the endpoints by mechanical dyssynchrony (≤0.62 for all parameters). The results suggested that measures of mechanical dyssynchrony had limited incremental value in patient selection, including those indices derived from TDI that had demonstrated a large body of evidence before PROSPECT [6,7]. Of note, the PROSPECT study had a number of major limitations in the design and execution which raised further controversies and biased the conclusion [8—11]. The trial commenced in 2003 when the implantation technique of CRT devices became quite mature due to systematic proctoring, hands-on training, and high-volume implantation in centers selected and supported by device companies. On the contrary, there were only a few laboratories in the world that regularly performed dyssynchrony analysis by echocardiography at that time where knowledge sharing and hands-on training had yet to develop. Inevitably, some technical problems were introduced in this study, including methodology in dyssynchrony assessment by offline analysis was not standardized, training was inadequate, and echocardiographic equipment was not uniform and in some centers too obsolete for adequate TDI images. Dyssynchrony measurements adopted in the PROSPECT trial were criticized by their unexpected high interobserver variabilities, which ranged from 32% to 72% and intraobserver variabilities from 16% to 24%, presented by the reproducibility test within the core laboratories [6]. This may reflect the general difficulty in dyssynchrony analysis by echocardiography. However, it is worth mentioning that the variability test was conducted retrospectively after all the offline analysis had been completed, but not before the study. It is arguable that these 3 core laboratories should have been trained and adopted a common algorithm for dyssynchrony analysis before offline analysis was commenced. Of note, the interobserver variability for the measurement of LVESV by Simpson’s method was as high as 14.5% [6]. Moreover, in about half of the images, the image quality was not adequate for offline TDI analysis. Consequently, concerns are raised that ‘‘failure’’ of mechanical dyssynchrony by echocardiography could be attributed to the lack of standards in online acquisition and offline analysis due to insufficient training and feedback between the core laboratories and the study sites, in particular during the initial phase of the trial. Furthermore, the use of modern echocardiographic equipment capable of decent TDI image quality cannot be overemphasized. Therefore, the PROSPECT trial should not be regarded as a final conclusion that dyssynchrony has little role in predicting CRT response, but rather, an appeal to physicians to emphasize training with knowledge and skill transfer if the role of echocardiographic dyssynchrony is to be explored, sim-

Mechanical dyssynchrony predicts CRT ilar to the case when CRT device implantation was under development.

New evidence for mechanical dyssynchrony in CRT LV mechanical dyssynchrony refers to the delay in the timing of contraction of some myocardial segments within the LV, also known as intraventricular dyssynchrony, which commonly occurs in heart failure patients. The analysis of intraventricular dyssynchrony is accomplished commonly by echocardiography, which ranges from conventional Mmode and Doppler echocardiography to more advanced TDI, real-time three-dimensional echocardiography (RT3DE), and two-dimensional speckle tracking imaging (2DSTI), and most of the time, is performed at rest [12]. Its presence is related not only to the QRS duration, but also with the loading condition, etiology of heart failure, severity of coronary artery disease, and degree of LV remodeling. As previously reported, mechanical dyssynchrony is not detected in about one-third of heart failure patients with a wide QRS complex (≥120 ms) as a marker of electrical dyssynchrony, and conversely, it is present in 40—50% of those with a narrow QRS complex (<120 ms) [13]. Therefore, the electrocardiographic criteria of QRS width ≥120 ms as in the current guideline for CRT are not ideal for identifying mechanical dyssynchrony which lead to suboptimal response rate [14].

Mechanical dyssynchrony at rest by echocardiography A number of studies were conducted in the post-PROSPECT era to examine the ability of mechanical dyssynchrony in predicting favorable responses after CRT [15—40]. Echocardiographic technologies adopted were mainly TDI, RT3DE, and 2DSTI for intraventricular dyssynchrony, and Doppler for interventricular mechanical delay (IVMD), the latter refers to the mechanical dyssynchrony between the contraction of the right and left ventricles. When compared with early studies in this field, recent studies have a few advancements which are worth mentioning. Although most of these studies were single-centered, a couple of them were conducted in 2 centers with common protocol and standardized technique of dyssynchrony analysis ensured. While we are waiting for more confirmative data derived from future multicenter trials that are well designed and executed, it is encouraging to look at a few 2- and 3-center studies where the feasibility of dyssynchrony assessment among different sites is verified as well as its predictive value in CRT. Secondly, the selection of primary endpoints in these trials was more appropriate with longer duration of follow up, by using mid-term reverse remodeling (i.e. LVESV reduction at 6 months) or long-term clinical outcome such as all-cause mortality and cardiovascular events. Although LV reverse remodeling could be regarded as a surrogate marker but not a hard endpoint, its occurrence after CRT has been proved to correlate with improvement in clinical status and favorable long-term prognosis [41,42]. Thirdly, the predictive value of mechanical dyssynchrony by echocardiography was tested in a multivariate model with

241 the inclusion of other possible predictors at baseline such as age, gender, etiology of heart failure, severity of mitral regurgitation, presence of atrial fibrillation, and LV lead position [43—47]. Table 1 lists the studies published online from June 2008 to December 2010 which examined the role of mechanical dyssynchrony in predicting CRT response, and had a large sample size of over 100 patients. From their results, mechanical dyssynchrony was able to independently predict LV reverse remodeling or better clinical outcome after CRT in all but one study. The only negative study published by Miyazaki et al. showed that the 14 tested dyssynchrony parameters failed to predict the reduction of LVESV in non-ischemic patients, while only in ischemic patients LV reverse remodeling had a modest association with M-mode, tissue Doppler strain and time interval indices [22]. Although a number of indices for mechanical dyssynchrony have been proposed and adopted in clinical trials, there is little consensus on which is the best for clinical use [12,34,35,48—51]. This might be attributed to the lack of consistent result from limited studies on headto-head comparison, and the expertise dependence of a particular technique. Consequently, combination of dyssynchrony parameters by different imaging modalities has been suggested. The study by Gorcsan et al. suggested the superiority of combining longitudinal dyssynchrony index by TDI and radial dyssynchrony index by 2DSTI [52]. From their study, a 15% increase in ejection fraction (EF) was observed in 95% of patients who had both longitudinal and radial dyssynchronies, while the EF response occurred in only 10% of patients with neither longitudinal nor radial dyssynchrony. Recently, a multiparametric strategy with the inclusion of more indices was tested in CRT population. In the study where the atrioventricular dyssynchrony, IVMD, and intraventricular dyssynchrony that integrated radial and longitudinal measurements for spatial and temporal dyssynchronies were investigated as 8 parameters, it appeared that the combination of 2—4 parameters increased the percentage of CRT responders by decreasing the number of false-positive cases [18]. Nevertheless, these studies were mainly focused on specificity, i.e. to increase the responder rate by identifying possible non-responders, leaving sensitivity to a less important place. With the increase in specificity by adding more parameters, sensitivity of such a strategy was markedly reduced where many patients would be deprived of the therapy by falling into false-negative cases. Because of the complexity in LV mechanics, a diverse pattern has been described for dyssynchrony expression in different components or directions [18,53,54]. In a recent study by Zhang et al. which enrolled 488 heart failure patients from 2 cardiac centers with EF ≤ 35%, the presence of both longitudinal dyssynchrony by TDI and radial dyssynchrony by 2DSTI was only noted in 28% of the study population [54]. Therefore, to predict non-responders to CRT, simply combining two or more dyssynchrony indices might not be the solution ahead. Rather, a more comprehensive predictive algorithm which includes other non-dyssynchrony-related factors may provide a better balance between sensitivity and specificity.

Mechanical dyssynchrony by echocardiography in predicting responses after cardiac resynchronization therapy.

Author [Ref. no.]

Patient (n)

EF and QRS width

Follow up

Dyssynchrony indices

Endpoints

Major findings

Lim [15]

100

26 ± 9% 154 ± 29 ms

3 months

Longitudinal strain delay index by 2DSTI

LVESV reduction > 15%

*The index ≥ 25% identified 82% of responders and 92% of nonresponders *It correlated with reverse remodeling

Clelanda [16]

813

<35% ≥120 ms

37.6 months

IVMD by Doppler

All-cause mortality

Less IVMD at baseline predicted a worse outcome (chi-square: 8.8, p = 0.0029)

Zhangb [17]

239

<35% >120 ms

37 ± 20 months

The maximal delay in Ts by TDI (4 segments)

Cardiovascular mortality

The maximal delay (HR 0.46) and ischemic etiology (HR 2.716) were independent predictors of cardiovascular mortality

Lafitteb [18]

200

25 ± 8% 152 ± 17 ms

6 months

LVESV reduction ≥15%

Positivity in more than 3 parameters associated with a specificity >90% and a positive predictive value >65%

van Bommel [19]

361

23 ± 7% 169 ± 24 ms

6 months

8 indices: atrioventricular interventricular intraventricular Ts-S-L by TDI

Ts-S-L ≥ 65 ms was an independent predictor of both clinical and echocardiographic response

Oyenuga [20]

221

≤35% 100—130 ms in 86 patients >130 ms in 135

6 months

IVMD longitudinal delay by TDI radial delay by 2DSTI

*Improvement of NYHA class ≥1 *LVESV reduction ≥15% *EF increase ≥15% *LVESV reduction ≥10%

van Bommel [21]

716

25 ± 19 months

Ts-S-L by TDI

All-cause mortality

Ts-S-L ≥ 65 ms was associated with a better survival (HR 0.65)

Miyazaki [22]

131

25% (19—31%) 167 ms (136—179 ms) 25 ± 7% 175 ± 29 ms

6 months

LVESV reduction ≥ 15%

*In nonischemic, no index predictive *In ischemic, M-mode (AUC 0.67), tissue Doppler strain (AUC 0.79), and isovolumic time (AUC 0.76)-derived indices predictive although the incremental value was modest

van Bommelb [23]

123

27 ± 7% <120 ms

6 months

LVESV reduction ≥ 15%

Longitudinal delay > 75 ms and radial delay > 107 ms demonstrated usefulness in predicting reverse remodeling after CRT

Gorcsan [24]

229

≤35% ≥120 ms

4 years

14 indices: M-mode tissue Doppler velocity tissue Doppler strain 2D speckle strain RT3DE time intervals 5 indices: LV filling ratio LV pre-ejection time IVMD longitudinal delay by TDI radial delay by 2DSTI Ts-SD by TDI Trs-AS-P by 2DSTI IVMD

Free from death, transplantation or LV assist device

*Ts-SD and Trs-AS-P independently associated with outcome *Trs-AS-P useful in QRS of 120—150 ms

242

Table 1

Radial dyssynchrony ≥ 130 ms was predictive of EF response in both wide QRS patients (88% sensitivity, 74% specificity) and borderline QRS patients (79% sensitivity, 82% specificity)

Q. Zhang, C.M. Yu

2D, two-dimensional; 2DSTI, two-dimensional speckle tracking imaging; AUC, area under the curve; CRT, cardiac resynchronization therapy; EF, ejection fraction; IVMD, interventricular mechanical delay; HR, hazard ratio; LV, left ventricular; LVESV, left ventricular end-systolic volume; NYHA, New York Heart Association; RT3DE, real-time three-dimensional echocardiography; TDI, tissue Doppler imaging; Trs-AS-P, the septoanterior to posterior delay in the time to peak radial strain; Ts-SD, the standard deviation of the time to peak systolic velocity among the 12 LV segments; Ts-S-L, the septal to lateral delay in the time to peak systolic velocity. * represents multiple items of endpoints or major findings. a Multicenter study. b 2-,3-Center study.

Tanakab [25]

132

≤35% ≥120 ms

3.5 years

Short-axis radial strain and transverse strain delay by 2DSTI

*Mid-term EF response *Long-term events as death, transplant, or LV assist device

*Sensitivity (86%) and specificity (67%) higher for radial strain in predicting EF *Unfavorable clinical events higher in patients with neither radial nor transverse dyssynchrony (53%) than in those with both baseline dyssynchrony (12%)

Mechanical dyssynchrony predicts CRT

243

Mechanical dyssynchrony during stress echocardiography Recently, it appears that the assessment of LV mechanical dyssynchrony at rest may not be adequate in heart failure patients since exacerbation of symptoms, increase in mitral regurgitation, and reduction in exercise capacity are found to be related to exercise-induced dyssynchrony in a few pilot studies, as shown in Table 2 [55—60]. These studies investigated the impact of exercise on mechanical dyssynchrony, most of which made use of TDI, and revealed a large variation in dynamic dyssynchrony from patient to patient, i.e. increased in some patients, remained unchanged in some, and decreased in the others. Interestingly, either dyssynchrony measure at peak exercise or the rest−exercise difference in dyssynchrony was associated with clinical outcomes, which was superior to dyssynchrony at rest alone. Having observed the changes in mechanical dyssynchrony caused by exercise, on a closer inspection, we could categorize heart failure patients into 4 different groups, i.e. those without dyssynchrony at rest, but induced by exercise (true exercise-induced dyssynchrony), those with dyssynchrony at rest, but normalized on exercise (true exercise-normalized dyssynchrony), those without dyssynchrony at rest and during exercise, as well as those with dyssynchrony in both situations. Nevertheless, concerns have been raised on the ratio of patients in these groups and who may potentially benefit from CRT. In the study by Lafitte et al., the authors suggested that the exercise-induced and exercisenormalized groups that might warrant further investigation in CRT candidates to help understand the relationship with treatment response constituted 20—26% of the study population [55]. In their pioneer study, Rocchi et al. demonstrated that dyssynchrony measured by TDI at peak exercise was a better predictor of functional improvement and LV reverse remodeling at 6 months than resting dyssynchrony [61]. This study enrolled 64 patients with class III or IV heart failure symptoms scheduled for CRT, in whom dyssynchrony assessment was performed both at rest and during exercise by using the TDI derived septal-to-lateral delay in the time to peak systolic velocity. Mechanical dyssynchrony was present in 40 (63%) patients at rest and in 46 (72%) at peak exercise. The degree of improvement in LVESV or EF was more obvious in patients with exercise dyssynchrony than those with exercise synchrony, while the difference was not so obvious between patients with and without resting dyssynchrony. Recently, the use of low-dose dobutamine stress echocardiography (DSE) was suggested by Parsai et al. for the assessment of dynamic mechanical dyssynchrony before CRT [62]. An early and short-lived septal motion as a marker of mechanical dyssynchrony (septal flash), was measured by its presence and excursion at rest and during DSE, and was correlated with LV reverse remodeling response. Intriguingly, all patients with a septal flash at rest were volumetric responders who also showed a significant increase in septal flash excursion at peak stress, both of which were totally abolished after CRT. On the other hand, 5 (24%) patients among those without a detectable septal flash at rest who developed a new septal flash during stress (true stress-induced dyssynchrony) responded to the therapy [62]. Nevertheless, more clinical trials with larger sample size are warranted to

244

Table 2

Modifications of mechanical dyssynchrony during exercise in heart failure patients.

Author [Ref. no.]

Patient (n)

EF and QRS

Dyssynchrony indices

Dyssynchrony at rest

Dyssynchrony during exercise

Correlation between dyssynchrony and clinical endpoints

Lafitte [55]

65

<35% Any

Ts-SD by TDI

Occurred in 60% of the patients

The rest−exercise difference in Ts-SD associated with the change in CO (r = −0.63) and MR (r = 0.56)

D’Andrea [56]

60

<35% <120 ms

Ts-SD by TDI

Occurred in 33.3% of the patients

*Occurred in 62% *Increased in 34%, remained in 37%, decreased in 29% *Exercise induction or normalization in 26% *Occurred in 58.3% *Increased in 76.7%, remained in 5%, decreased in 18.3%

Wang [57]

33

<35% ≤120 ms

Ts-SD by TDI

None

Occurred in 33%

Higher LV filling pressure by E/Ea > 10 at rest, independently predicted the exercise-evoked dyssynchrony

Lancellotti [58]

57

<50% Any

Ts-SD by TDI

Prevalence not reported

Increased in about 50%, no change or decreased in 50%

Ts-SD at peak exercise independently predicted the exercise-induced increase in BNP

Kang [59]

41

<40%

Ts-SD by TDI

Occurred in 39% of the patients

Prevalence not reported but variable changes noted

Ts-SD at peak exercise predicted the improvement in LVESV (ˇ = 0.577) and EF (ˇ = −0.563)

Izumo [60]

50

<45% Any

SDI by RT3DE

Prevalence not reported

*Prevalence not reported *Mean value of SDI raised in the group with increased MR

The changes in SDI and in MR were correlated (ˇ = −0.53)

The changes in Ts-SD and in mitral valve ERO (ˇ = 0.62), in stroke volume (ˇ = −0.53) were correlated

BNP, brain natriuretic peptide; CO, cardiac output; E/Ea , transmitral E velocity to mitral annular velocity ratio; EF, ejection fraction; ERO, effective regurgitant orifice; LV, left ventricular; LVESV, left ventricular end-systolic volume; MR, mitral regurgitation; RT3DE, real-time three-dimensional echocardiography; SDI, systolic dyssynchrony index; TDI, tissue Doppler imaging; Ts-SD, the standard deviation of the time to peak systolic velocity among the 12 LV segments.

Q. Zhang, C.M. Yu

Mechanical dyssynchrony predicts CRT investigate the role of dynamic dyssynchrony in CRT population.

Mechanical dyssynchrony by other imaging modalities In addition to echocardiography, cardiac magnetic resonance (CMR) and nuclear imaging with single photon emission computed tomography (SPECT) have been evaluated for the assessment of mechanical dyssynchrony in CRT candidates [63—71]. CMR allows high-resolution, reproducible and three-dimensional wall motion tracking in circumferential, radial, and longitudinal dimensions, and provides information on myocardial strain, velocity, twist, and torsion. There are several methods for assessing dyssynchrony using CMR, which include myocardial tagging, strain-coded CMR, three-dimensional tagged CMR, and CMR tissue synchronization imaging (CMR-TSI). In a study where 77 patients with an EF < 35% and a QRS ≥ 120 ms were followed up for a mean of 764 days after CRT, CMR-TSI ≥ 110 ms at baseline indicated a 5.2 times higher likelihood of allcause mortality or hospitalization for a major cardiovascular event [64]. By combining with delayed enhancement CMR (DE-CMR) that offers precise characterization of myocardial scar, assessment of LV mechanical dyssynchrony and scar extent could be performed in a single session and tested for their relative merits in CRT. In two small-scale studies, mechanical dyssynchrony was found to correlate with functional improvement or LV reverse remodeling after CRT, and the addition of scar measurement by DE-CMR further improved the predictive value [65,66]. Using nuclear imaging, assessment of mechanical dyssynchrony is usually performed with gated blood-pool ventriculography and phase analysis [69—71]. The study by Boogers et al. enrolled 40 patients with an EF ≤ 35% and a QRS ≥ 120 ms who had New York Heart Association (NYHA) class III or IV symptoms and were scheduled for CRT implantation. Dyssynchrony parameters by SPECT as histogram bandwidth (r = 0.69) and phase SD (r = 0.65) were significantly associated with the septal-to-lateral delay in the time to peak systolic velocity using TDI. At baseline, CRT responders with an improvement in NYHA of one class or more showed a significantly larger histogram bandwidth (94 ± 23◦ vs 68 ± 21◦ ) and a larger phase SD (26 ± 6◦ vs 18 ± 5◦ ) than non-responders. From the receiver operating characteristic curves, a cut-off value of 72.5◦ for histogram bandwidth and a cut-off value of 19.6◦ for phase SD predicted CRT responses, yielding a similar sensitivity of 80% and specificity of 80% [69]. The results also corroborated an earlier study by Henneman et al. with a similar study population and SPECT analysis method employed where a different cut-off value was derived from another algorithm [70].

Conclusion Mechanical dyssynchrony remains to be the most likely target of CRT, which could not be simply reflected by QRS duration. Echocardiography, in particular those advanced quantitative techniques for regional wall motion that include TDI, RT3DE and 2DSTI, can help to understand the complexity of LV mechanics and therefore identify

245 more appropriate patients to receive CRT. The results of the PROSPECT trial could not be regarded as the final answer by virtue of its multicenter nature where a number of issues in study design and conduction are raised. In the post-PROSPECT era, mechanical dyssynchrony remains a determinant for mid-term cardiac improvement and long-term clinical outcome after CRT in many stringently conducted clinical trials. Furthermore, its merit shall be evaluated in a more comprehensive predictive model with other factors such as scar burden, LV lead position, etiology of heart failure, mitral regurgitation, and potentially beyond. Continuous enthusiasm and support to quest for better predictor(s) of CRT response will render the therapy cost-effective as well as identify new potential patient group(s) that might benefit from CRT.

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