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rchives of Cardiovascular Disease (2009) 102, 469—472

CIENTIFIC EDITORIAL

an real-time three-dimensional echocardiographye used reliably for the assessment of leftentricular dyssynchrony?�

st-ce que l’échographie tridimensionnelle peut être utilisée de facon fiableans l’évaluation d’un asynchronisme ventriculaire gauche ?

Richa Agarwal, John F. Beshai, Roberto M. Lang ∗

Section of Cardiology, University of Chicago Medical Center, 5841, South Maryland Avenue,MC 5084, 60637 Chicago, USA

Received 14 May 2009; accepted 15 May 2009Available online 4 July 2009

KEYWORDSBiventricular pacing;Three-dimensionalechocardiography;Dyssynchrony

MOTS CLÉSStimulationbiventriculaire ;

Abbreviations

CRT cardiac resynchronization therapyLV left ventricle/ventricularLVEF left ventricular ejection fractionRT3DE real-time three-dimensional echocardiographySDI systolic dyssynchrony indexTDI tissue Doppler imaging

The assessment of LV dyssynchrony through a variety of advanced imaging modalities hasgarnered substantial interest, as current dyssynchrony markers remain equivocal for pre-

Échocardiographietridimensionnelle ;Asynchronisme

dicting response to CRT in patients with advanced heart failure. Current recommendationssupport the use of CRT in symptomatic patients with moderate-to-severe heart failure, NewYork Heart Association functional class III or IV, QRS duration greater or equal 120 ms and anejection fraction less or equal to 35%, who have been optimized with medical therapy. Thisdevice-based therapy has important therapeutic benefits, including functional and clinical

� Additional value of three-dimensional echocardiography in patients with cardiac resynchronization therapy, Deplagne A., Bordachar P.,eant P., Montaudon M., Reuter S., Laborderie J., Dos Santos P., Roudaut R., Jais P., Haissaguerre M., Laurent F., Clementy J., Lafitte S.,doi:10.1016/j.acvd.2009.03.013.∗ Corresponding author. Fax: +1 773 702 1034.

E-mail address: rlang@medicine.bsd.uchicago.edu (R.M. Lang).

875-2136/$ — see front matter © 2009 Elsevier Masson SAS. All rights reserved.oi:10.1016/j.acvd.2009.05.002

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mprovements, significant reverse LV remodelling and anncrease in ejection fraction on echocardiography, and mostmportantly, improved survival. QRS duration is an electri-al surrogate for dyssynchrony and is the current standardariable used for patient selection; however, the 30—40%on-responder rate underscores the need for a more pow-rful and specific criterion for mechanical dyssynchrony.better understanding of device-related factors that may

ffect post-implantation response directly is also required.lthough no echocardiographic dyssynchrony variable toate can predict response more accurately than or supplanthe current selection criteria, the role of imaging for CRTandidates is gaining momentum rapidly, and the successfulevelopment and validation of newer modalities for assess-ng dyssynchrony will have a great impact on future clinicalractice.

Colour TDI assessment of LV dyssynchrony is the mostxtensively studied echocardiographic method and a num-er of established TDI criteria have been shown in smalltudies to be highly predictive for CRT response. Well-knownDI velocity-based indices include the Yu index, which is thetandard deviation of time-to-peak systolic velocity of 12 LVegments, and the Bax index, which analyses velocity delayetween the four basal segments in the longitudinal plane1,2]. Despite good experience with this two-dimensionalpplication, TDI has a number of limitations, including anngle-dependency that permits assessment of timing ofotion in the longitudinal plane only, an inability to dif-

erentiate between passive motion or tethering and activeotion, and non-simultaneous assessment of different LV

egments. The focus on longitudinal assessment with TDIreates a significant disadvantage, as this is an incompleteV motion analysis and is subject to greater variability. Fur-hermore, when a variety of TDI variables were tested withigh-quality control in the large, prospective, multicen-re predictors of response to CRT (PROSPECT) study, theyere found to have only modest specificity and sensitivity

or predicting clinical response or reverse LV remodelling.he conclusions from the study were that TDI methods cane technically challenging and poorly reproducible and canield equivocal results when attempted widely. In addition,DI dyssynchrony variables have not been advantageous forroving benefit with CRT in specific heart failure popula-ions, such as in patients with narrow QRS width. Newermaging methods may offer insight into the complex rela-ionship of electromechanical delay in this group.

To overcome the limitations of TDI, RT3DE has emergeds a newer method that offers a comprehensive and simul-aneous assessment of intraventricular dyssynchrony. Inhis issue of Archives of Cardiovascular Diseases, Deplagnet al. describe in a small, prospective study how three-imensional assessment of ventricular dyssynchrony canrovide additional benefit to two-dimensional dyssynchronyssessment in predicting response with biventricular pac-ng [3]. This study, like others, capitalizes on the potentialdvantages of RT3DE. Three-dimensional dynamics of thentire LV, with angle-independent information about radial,

ircumferential and longitudinal timing, can be obtainedn a single recording with this method. Resynchronization,mprovement in ejection fraction and a reduction in LV end-ystolic volume, which is better for predicting improvedurvival with CRT [4], can also be assessed quickly and

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epeatedly with RT3DE during long-term follow-up. Indeed,T3DE offers accurate ejection fraction and volumes esti-ations that are similar to magnetic resonance imaging andetter than two-dimensional imaging. Potential disadvan-ages of this method are related largely to its novelty andngoing development. Concerns over poor image quality andow frame rates with RT3DE, the potential for disagreementnd imperfect translation between multiple software sys-ems used for three-dimensional analysis, the conflictingesults of validation studies and the lack of clearly estab-ished normal values still need to be resolved.

RT3DE dyssynchrony assessment is performed by tracingndocardial borders manually to create a three-dimensionaleconstruction or ‘‘shell’’ of the LV. This LV model is thenubdivided into 16 or 17 volumetric segments and the vol-me changes in each segment are calculated throughouthe cardiac cycle. The dispersion in the times to minimumystolic volume attainment for each segment is taken andhen superimposed as time—volume curves. Synchronousontraction implies that most segments will achieve mini-um volume at the same time point in the cardiac cycle,

nd thus the time—volume curves for each region will beligned. In a patient with significant dyssynchrony, the timeoints, depicted by the curves, will appear non-uniformnd misaligned. Kapetanakis et al. developed a SDI (thetandard deviation of the 16 segments’ time to minimum sys-olic volume attainment, expressed as a percentage of theardiac cycle) to calculate the degree of global LV dyssyn-hrony [5]. A higher SDI indicates greater intraventricularyssynchrony, although cut-off values for significant dyssyn-hrony to predict CRT response are yet to be determined.he methodology of RT3DE has been advanced by new soft-are algorithms designed to improve the delineation of LVorders, in order to minimize errors and the introductionf artefacts from the manual correction of the endocardialoundary. In addition, colour-coded parametric imaging ispplied to the three-dimensional data to reveal maximumyssynchrony between the areas of early and latest acti-ation. These displays are highly intuitive, and desirablerom an electrophysiologist’s perspective, to help guide leadlacement that is concordant with the site of latest mechan-cal activation.

Current normal values have been proposed in severalmall studies and are notably different. This may bexplained in part by whether the LV segmentation modeln these studies includes the apical cap, irrespective ofhether this segmentation model is defined as having 16r 17 segments. Kapetanakis et al. set out to define theyssynchrony index in normal patients (mean SDI 3.5 ± 1.8%,ith an arbitrary cut-off for dyssynchrony greater than

hree standard deviations above this mean, or 8.3%) in a6-segment model in which the apical cap was includednd divided among four apical segments. This study provedhat significant differences in the SDI exist between groupsith mild, moderate and severe LV dysfunction. SDI corre-

ated in a strong logarithmic fashion with worsening LVEF,ndependent of QRS duration, and was significantly highern responders to CRT compared with non-responders [5].

he negative correlation between the dyssynchrony indexnd LVEF, irrespective of QRS width, has been confirmedy another study (r = −0.91), which also sought to definen abnormality threshold for dyssynchrony in patients with

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Assessment of left ventricular dyssynchrony by three-dimen

dilated cardiomyopathy, with and without left bundle branchblock, across a wide range of ages. The abnormality thresh-old here was lower than in the study by Kapetanakis et al.and was defined as 4.0% (mean plus two standard devia-tions of the normal controls) in a 16-segment model thatexcluded the apical cap entirely. This threshold was alsofound to be age- and sex-independent [6]. Furthermore, adifferent group of investigators found that a cut-off SDI of5.6% had a moderately high sensitivity and specificity forpredicting acute improvement in LV volumes with CRT [7].Deplagne et al. quantified the SDI as the standard devia-tion of 17 segments and showed that the three-dimensionalSDI was significantly higher in responders compared with innon-responders, although echocardiographic response herewas defined by a 10% reduction in LV end-systolic volumeand not 15% as in other studies. Significant improvementin this index occurred after device implantation and inter-ventricular delay optimization, although this trend was notexploited further to derive normal values or a cut-off valuefor predicting CRT response.

For this method to gain acceptance, larger multicentrestudies are needed to define normal values and an abnor-mal threshold that can identify candidates for CRT reliably.The discrepancy between using a 16-segment model (with-out apical cap) and 17-segment model (with apical cap)for dyssynchrony assessment also warrants clarification. Theapical cap, which is used mainly in perfusion analysis, con-tributes little to overall ejection fraction and has minimalendocardial excursion, which can make measurement oftime to minimum volume difficult in this region. Includ-ing the apex may therefore confound dyssynchrony analysis,making a 17-segment model less specific and less preferablethan a 16-segment model that excludes the apical cap [6].On a similar theme is the issue of how to incorporate dysk-inetic or akinetic areas in the dyssynchrony analysis, as wemust first understand how such segments can shift the SDIand affect the accuracy of this method. A ‘‘weighted’’ SDIthat places higher value on viable segments, and on regionsthat contribute the most towards systolic performance (i.e.the basal segments), may be a more rational way of quanti-fying dyssynchrony.

Because most experience is with TDI, and because sev-eral TDI variables have been related to favourable response,studies comparing RT3DE with TDI have sought to validatethis newer technique. Kapetanakis et al. found only a mod-erate correlation (r = 0.38) between RT3DE and TDI for allpatients when using the SDI cut-off value of 8.3% for sig-nificant dyssynchrony. Burgess et al. found similar resultsin 100 patients with ischaemic cardiomyopathy, with a poorcorrelation (r = 0.11) between RT3DE and TDI dyssynchronyassessment in a 12-segment model, although they used thesame SDI cut-off of 8.3% defined previously by Kapetanakiset al. [8]. This study showed that RT3DE identified a smallernumber of patients with dyssynchrony than TDI, but perhapsa cut-off value of 8.3%, with its specificity of 100% but sen-sitivity of only 46%, may be too high to apply to a normalpopulation [7]. In contrast to the findings by Kapetanakis

et al. and Burgess et al., other studies have shown a fairdegree of correlation between TDI and RT3DE. MultipleRT3DE dyssynchrony indices, including time to minimum sys-tolic volume for 6-, 12- and 16-segment models, were shownin a study of 122 patients by Takeuchi et al. to have good

l echocardiography 471

orrelation (r = 0.71) and a concordance rate of 79% with aDI index of dyssynchrony, specifically the standard devi-tion of time to peak systolic velocity of 12 LV segments.orrelation between RT3DE and TDI improved when a largerumber of segments, such as in the 16-segment model, weresed [9]. When RT3DE was compared with phase analysis ofingle photon emission computed tomography perfusion foryssynchrony quantification in a small number of patients, aood correlation (r = 0.80) was observed [10]. Studies haveroduced conflicting results for validation of RT3DE, butt should be emphasized that without a gold standard and

clear cut-off value for SDI, proper comparison betweenethods may not be possible. Furthermore, poor correlationetween these methods is not entirely surprising, as TDI andT3DE evaluate dyssynchrony in different directional planesnd focus on distinct systolic indices and timings, with TDIvaluating peak tissue velocities in early systole and RT3DEvaluating minimum volumes as an expression of endocar-ial excursion in end systole. Few studies such as the oney Deplagne et al. have directly compared RT3DE and TDIndices of dyssynchrony for predicting clinical response andeverse remodelling after CRT, which is after all one of theore meaningful questions for understanding the true merit

f RT3DE.There are several technical considerations for improv-

ng the use of RT3DE. Endocardial tracking, the first stepowards creating a three-dimensional shell, depends onxcellent imaging resolution. Improved imaging transduc-rs are needed to produce high image quality and averthe need for manual adjustments of border contours.eplagne et al. acknowledge the difficulty of endocar-ial tracking in patients with poor ultrasonic windows.he authors also mention the drawbacks of using different

maging machines for making two-dimensional and three-imensional dyssynchrony measurements. This could affectomparisons between modalities, particularly in studiesith a small number of subjects. We agree with theseuthors that good interobserver agreement and repro-ucibility of RT3DE dyssynchrony measurements acrosschocardiography laboratories need to be confirmed beforeonfidence in this method is gained and implementation canccur.

RT3DE is a promising advanced imaging modality foryssynchrony assessment and for accurate evaluation of LVeverse remodelling with CRT. Rigorous validation of RT3DEnd the clear establishment of cut-off values are neededefore we can implement this technology and potentiallymprove the practice of selecting patients for CRT.

eferences

[1] Bax JJ, Bleeker GB, Marwick TH, et al. Left ventriculardyssynchrony predicts response and prognosis after cardiacresynchronization therapy. J Am Coll Cardiol 2004;44:1834—40.

[2] Yu CM, Fung WH, Lin H, et al. Predictors of left ventricularreverse remodeling after cardiac resynchronization therapy for

heart failure secondary to idiopathic dilated or ischemic car-diomyopathy. Am J Cardiol 2003;91:684—8.

[3] Deplagne A, Bordachar P, Reant P, et al. Additional value of3-dimensional echocardiography in patients with cardiac resyn-chronization therapy. Arch Cardiovasc Dis 2009 (this issue).

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[4] Yu CM, Bleeker GB, Fung JW, et al. Left ventricular reverseremodeling but not clinical improvement predicts long-termsurvival after cardiac resynchronization therapy. Circulation2005;112:1580—6.

[5] Kapetanakis S, Kearney MT, Siva A, et al. Real-time three-dimensional echocardiography: a novel technique to quantifyglobal left ventricular mechanical dyssynchrony. Circulation2005;112:992—1000.

[6] Sonne C, Sugeng L, Takeuchi M, et al. Real-time threedimensional echocardiographic assessment of left ventriculardyssynchrony in normal subjects and in patients with dilated

cardiomyopathy: redefinition of abnormality. JACC CardiovascImaging 2009; 2:802—12.

[7] Marsan NA, Bleeker GB, Ypenburg C, et al. Real-timethree-dimensional echocardiography permits quantification ofleft ventricular mechanical dyssynchrony and predicts acute

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response to cardiac resynchronization therapy. J CardiovascElectrophysiol 2008;19:392—9.

[8] Burgess MI, Jenkins C, Chan J, et al. Measurement of leftventricular dyssynchrony in patients with ischaemic cardiomy-opathy: a comparison of real-time three-dimensional and tissueDoppler echocardiography. Heart 2007;93:1191—6.

[9] Takeuchi M, Jacobs A, Sugeng L, et al. Assessment ofleft ventricular dyssynchrony with real-time 3-dimensionalechocardiography: comparison with Doppler tissue imaging. JAm Soc Echocardiogr 2007;20:1321—9.

10] Marsan NA, Henneman MM, Chen J, et al. Real-time three-

dimensional echocardiography as a novel approach to quantifyleft ventricular dyssynchrony: a comparison study with phaseanalysis of gated myocardial perfusion single photon emis-sion computed tomography. J Am Soc Echocardiogr 2008;21:801—7.