cardiac resynchronization therapy in paediatric and congenital

REVIEW

Frontiers in cardiovascular medicine

Cardiac resynchronization therapy in paediatricand congenital heart disease patientsAnnelies E. van der Hulst1, Victoria Delgado2, Nico A. Blom1, Nico R. van de Veire2,Martin J. Schalij 2, Jeroen J. Bax2*, Arno A.W. Roest1, and Eduard R. Holman2

1Department of Paediatric Cardiology, Leiden University Medical Center, Leiden, The Netherlands; and 2Department of Cardiology, Leiden University Medical Center, Albinusdreef2, 2333 ZA Leiden, The Netherlands

Received 19 October 2010; revised 14 January 2011; accepted 4 March 2011; online publish-ahead-of-print 30 March 2011

The number of patients with congenital heart disease (CHD) has significantly increased over the last decades. The CHD population has ahigh prevalence of heart failure during late follow-up and this is a major cause of mortality. Cardiac resynchronization therapy (CRT) may bea promising therapy to improve the clinical outcome of CHD and paediatric patients with heart failure. However, the CHD and paediatricpopulation is a highly heterogeneous group with different anatomical substrates that may influence the effects of CRT. Echocardiography isthe mainstay imaging modality to evaluate CHD and paediatric patients with heart failure and novel echocardiographic tools permit a com-prehensive assessment of cardiac dyssynchrony that may help selecting candidates for CRT. This article reviews the role of CRT in the CHDand paediatric population with heart failure. The current inclusion criteria for CRT as well as the outcomes of different anatomical subgroupsare evaluated. Finally, echocardiographic assessment of mechanical dyssynchrony in the CHD and paediatric population and its role in pre-dicting response to CRT is comprehensively discussed.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Cardiac resynchronization therapy † Congenital heart disease † Echocardiography

IntroductionHeart failure is a major health burden with an estimated overallprevalence of 2–3%.1 Cardiac resynchronization therapy (CRT)has improved the clinical outcome of drug refractory heartfailure in patients with poor left ventricular ejection fraction(LVEF) and wide QRS complex. CRT improves LV function byinducing a more synchronous contraction. Consequently, CRThas resulted in improvements in heart failure symptoms[New York Heart Association (NYHA) functional class, exercisecapacity or quality of life] and all-cause mortality of heart failurepatients.2 –7 Currently, CRT is a class I indication for patientswith NYHA functional class III or IV despite optimized pharmaco-logical therapy, LVEF , 35% and QRS duration .120 ms.8,9

Advances in cardiac surgery have led to an increased survival ofpatients with congenital heart disease (CHD). As a result, the preva-lence of CHD in the paediatric population has doubled over the lastdecades.10 Progressive heart failure is a major cause of death duringlate follow-up of patients with complex CHD.11,12 The excellentoutcomes obtained with CRT in adult patients have raised interestto apply this therapy in CHD and paediatric patients with heart

failure. However, the current inclusion criteria for CRT in adultpopulations may not be directly applied to paediatric patients.Aetiologies of heart failure differ substantially between adults andchildren, with CHD as the mainstay cause in the paediatric popu-lation.13 In addition, within the CHD population there are severalsubgroups of patients according to (post-surgical) cardiacanatomy, including patients with a systemic LV, patients with a sys-temic right ventricle (RV) and patients with a single ventricle.These different groups may show different responses to CRT.14 –

16 Therefore, a detailed evaluation prior to CRT implantation maybe crucial to identify those who will benefit from this therapywithin this heterogeneous group of patients.

Cardiac imaging plays a central role in the evaluation of CHDand paediatric patients before CRT device implantation. Accurateassessment of ventricular volumes and function is mandatorybefore CRT implantation to assess heart failure severity and toaccurately follow-up ventricular function. In addition, assessmentof cardiac anatomy is crucial to anticipate the ventricular pacinglead implantation approach (epicardial or transvenous). Further-more, the study of ventricular mechanical dyssynchrony and identi-fication of the latest activated areas may help to define the most

* Corresponding author. Tel: +31 71 5262020, Fax: +31 71 5266809, Email: [email protected]

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: [email protected].

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suited position of the ventricular pacing lead and may providemeaningful insight into the effects of CRT in the CHD and paedia-tric population. Several echocardiographic methods have beenproposed to evaluate ventricular mechanical dyssynchrony.17 Theassessment of ventricular dyssynchrony in the adult populationshas been demonstrated useful to identify patients who willbenefit from CRT, with subsequently a better clinical outcome.17

However, the role of established dyssynchrony parameters basedon tissue Doppler imaging (TDI), two-dimensional (2D) speckletracking and real-time three-dimensional (RT3D) echocardiogra-phy to evaluate mechanical dyssynchrony has not been extensivelystudied in the CHD and paediatric population.

This article reviews the role of CRT in chronic heart failure in theCHD and paediatric population, focusing particularly on the currentinclusion criteria and outcomes of different anatomical subgroups.Finally, the different imaging modalities to assess cardiac mechanicaldyssynchrony in the CHD and paediatric population and their role inpredicting response to CRT will be discussed.

Experience of cardiacresynchronization therapy incongenital heart disease andpaediatric patientsThe main CRT trials on CHD and paediatric patients have includedhighly heterogeneous populations. According to an anatomicalclassification, different subgroups can be defined, including patientswith:

systemic LV failure,systemic RV failure,failure of the single ventricle.

The group of patients with systemic LV failure (Figure 1A) consists ofboth paediatric patients with normal cardiac anatomy with heart

failure due to cardiomyopathies or congenital atrioventricular block,and of patients (children and adults) with LV failure due to underlyingCHD. Although the majority of evidence is based on case reports andsmall case series18–25 several retrospective non-randomized trialsincluding heterogeneous populations have reported favourable out-comes after CRT in this subgroup of patients.14–16

Failure of the systemic right ventricle (Figure 1B) is commonlyobserved in patients with complete transposition of the greatarteries who underwent atrial switch operation (Mustard orSenning procedure), and patients with congenital corrected transpo-sition of the great arteries (double discordance).26–28 A recent studyevaluated the effects of CRT in eight patients with systemic RVfailure. After a median follow-up of 17 months, RV ejection fractionsignificantly increased (mean change +10%, P ¼ 0.004), along witha decrease in QRS duration (from 161+21 to 116+22 ms, P ,

0.01).29 Subsequent small studies further demonstrated favourableclinical outcomes in RV systemic failure patients treated with CRT,yielding improvements in NYHA functional class, RV ejection frac-tion and exercise performance.14– 16,21,30–33

Finally, patients with failure of the single ventricle (Figure 1C) mayconstitute the most challenging population. According to current sur-gical practice, most patients with one hypoplastic ventricle undergosurgical palliation by a Fontan procedure or total cavo-pulmonaryconnection. The systemic and pulmonary circulations are separatedwithout interposition of a sub-pulmonary ventricle, and both cavalveins are redirected to the pulmonary artery. The ventricle support-ing the systemic circulation may be either of RV or LV morphology.Despite surgical intervention, heart failure is common in this sub-group of patients.28 Bacha et al.34 studied the effects of post-operativeCRT in 26 single-ventricle patients. Multisite epicardial pacing withmaximal distance between the wires yielded a significant reductionof QRS duration (from 94+18 to 72+11 ms, P , 0.01) and a sig-nificant improvement in cardiac function.

The different anatomical classification of CHD patients mayaccount for differences in response rates to CRT. In addition,

Figure 1 Anatomical subgroups of CHD and paediatric patients. (A) Example of a CHD patient with a systemic left ventricle. Apical four-camber view of a patient after correction of tetralogy of Fallot. The left ventricle is the systemic ventricle in patients with tetralogy ofFallot. The right ventricle is dilated in this patient due to pulmonary regurgitation and subsequent chronic volume overload. In tetralogy ofFallot, systemic left ventricular failure may occur during late follow-up. (B) Example of a CHD patient with a systemic right ventricle. Apicalfour-chamber view of a patient with congenital corrected transposition of the great arteries (double discordance). The (morphological)right ventricle is the systemic ventricle in patients with congenital corrected transposition of the great arteries. Note the trabecularizationof the systemic right ventricle and the (more apical) septal insertion of the atrioventricular valve compared with the (morphological) left ven-tricle. Systemic right ventricular failure is a common problem in patients with congenital corrected transposition of the great arteries. (C)Example of a CHD patient with a singe ventricle. Apical ‘four-chamber’ view of a patient with a hypoplastic left ventricle. The single ventricleis of right ventricular morphology. Note the very hypoplastic left ventricle. Failure of the single ventricle is common in patients with a hypo-plastic left ventricle. syst LV, systemic left ventricle; syst RV, systemic right ventricle; V, ventricle.

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cardiac anatomy may challenge lead implantation. In contrast to adultpatients with heart failure, a surgical epicardial approach is com-monly needed. Particularly, surgical epicardial lead implantationmay be preferred in small patients or in patients with a concomitantcardiac surgical indication. However, the three largest trials includingCHD and paediatric patients report no differences in complicationsduring CRT implantation or in clinical outcome between the patientswith transvenous or epicardial lead implantation.14– 16

Beyond the anatomical classification as described above, a sub-stantial part of the studies on CRT in paediatric and CHD patients

includes patients who previously underwent conventional single-site

pacing for congenital or surgical atrioventricular block.14 –16 In these

patients, chronic single-site ventricular pacing may cause failure of

the systemic ventricle at long-term follow-up.35– 38 Several smallseries have reported promising results with significant clinical andechocardiographic improvement after CRT upgrad-ing.21,24,25,30,32,33,39– 41 For example, Moak et al. describe a series ofsix patients with LV failure after long-term single-site pacing. Alongwith clinical improvement in all patients, LVEF significantly increased(from 34+6 to 60+ 2%, P ¼ 0.003) after upgrade to CRT.41

Outcome of cardiac resynchronizationtherapy in congenital heart diseaseand paediatric patientsBeyond case reports and small case series, data on mid- and long-term outcome, as well as survival and complication rates of CRT in

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Table 1 Retrospective cohorts on cardiac resynchronization therapy in congenital heart disease and paediatric patients

CRT studies in CHD and paediatric populations

Dubin et al.15 Cecchin et al.14 Janousek et al.16

Number of patients (n) 103 60 109

Age range (y) 0.3–55 0.4–43 0.2–74

median 13 15 17

Follow-up (mo) 4.8+4 Range: 1–64 Range: n/a

Median: 8.4a Median: 7.5

Before CRT

NYHA functional class n (%)

I 15 (14) 16 (27)

II 49 (48) 25 (42) Median: 2.5

III– IV 39 (38) 19 (32)

Systemic ventricle EF (%) 26+12 Range: 8–70 Range: n/aMedian: 36 Median: 27

QRS (ms) 166+33 Range: 95–210 Range: n/aMedian: 149 Median: 160

Successful implantations n (%) n/a 49 (82) 93 (85)

Complications n (%) 20b (19) 6 (10) 10 (9)

After CRT

NYHA functional class n (%) n/a n/a Median change -1.5

Systemic ventricle EF (%) 40+15* Range: n/a Median change +12Median: 43*

QRS (ms) 126+24* Range: n/a Range: n/aMedian: 120* Median: 130*

Response rates defined as

Systemic ventricle EF improvement n (%) 78 (76) n/a n/a

NYHA improvement ≥1 class n (%) n/a 19 (32) n/a

Systemic ventricle EF or NYHA improvement n (%) n/a 39 (65) 79 (72)

Survival rate n (%) 98 (95) 65 (92) 102 (94)

Data of three retrospective CRT studies in CHD and paediatric populations. Continuous data are expressed in means+ standard deviation unless otherwise specified. Responserates are on an intention to treat basis, i.e. including the total amount of patients enrolled in the study, regardless of deaths, follow-up, and unsuccessful implantations.Complications included: pocket haematomas, infection, lead issues, blood loss, ventricular arrhythmia, pneumothorax, pleural effusion, pulmonary oedema, cardiac perforation,cardiovascular incidents and pacing threshold problems.deaths, any deaths during follow-up period; EF, ejection fraction; mo, months; n/a, not available; NYHA, New York Heart Association functional class; successful implantation, allpatients alive and receiving CRT at latest follow-up date; y, years.*Statistical difference (P , 0.05) when compared with data before CRT implantation.aMajority of outcome data obtained at 3 months follow-up.bIncludes early complications (,30 days after CRT implantation).

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paediatric patients are limited to three retrospective studies includ-ing patients with all anatomical substrates and aetiologies (Table 1).

First, Dubin et al.15 described the outcomes of 103 CHD andpaediatric patients in a multicenter study. After a mean durationof 4.8 months follow-up, a reduction in QRS duration (from166+ 33 to 126+24 ms, P , 0.01) and an increase in ejectionfraction of the systemic ventricle (from 26+12 to 40+15%,P , 0.05) were observed after CRT. Finally, the survival rate inthis cohort was 95%.

Second, Cecchin et al.14 reported mid-term outcomes of 60CHD and paediatric patients treated with CRT. Significantimprovement in the ejection fraction of the systemic ventricle(from 36 to 43%, P , 0.01) and decrease in QRS duration (from149 to 120 ms, P , 0.01) were reported. A total of 65 (92%)patients survived during follow-up.

Third, Janousek et al.16 performed a multicenter trial on CRTincluding 109 CHD and paediatric patients. Similar to the otherseries, a significant improvement in ejection fraction of the sys-temic ventricle (from 27 to 39%, P , 0.01) and decrease in QRSduration (from 160 to 130 ms, P , 0.01) were noted. Finally,94% of patients survived during follow-up.

In these three studies, response rates (based on intention totreat) ranged between 32 and 76%, depending on the establishedendpoints. Dubin et al.15 reported a response rate of 76%,defined as an improvement in ejection fraction of the systemic ven-tricle. In the study by Cecchin et al.14, 32% of patients exhibited animprovement in NYHA functional class, and 65% of patientsimproved in either NYHA functional class or ejection fraction ofthe systemic ventricle. Finally, Janousek et al.16 defined responseas improvement in NYHA functional class or ejection fraction ofthe systemic ventricle and reported a response rate of 72%.

The different anatomical subgroups may account for differencesin the response rates to CRT. Response rates of the anatomicalsubgroups are depicted in Table 2. The majority of patients had asystemic LV (63–77%). Janousek et al.16 reported a responserate of 69% in this subgroup, defined by an increase in eitherLVEF or NYHA functional class.

The subgroup of patients with a systemic RV made up 15–29%of the cohorts (Table 2). Dubin et al.15 reported an improvement inNYHA functional class in 76% of this subgroup. In addition, defin-ing response rate by RV ejection fraction or NYHA functional classimprovement, the trial by Cecchin et al.14 reported a response rate

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Table 2 Response rates of retrospective cohorts on cardiac resynchronization therapy in congenital heart disease andpaediatric patients, according to anatomical subgroups

CRT studies in CHD and paediatric populations

Dubin et al.15 Cecchin et al.14 Janousek et al.a16

Systemic LV n (%) 79 (77) 38 (63) 62 (67)

Increase LVEF (%) n/a Median: 8* Median: 13*

Decrease QRS (ms) n/a Median: 33* Median: 40*

Response rate defined as

Increase LVEF n (%) n/a n/a n/a

NYHA improvement ≥1 class n (%) n/a n/a n/a

LVEF increase or NYHA improvement n (%) n/a n/a 43 (69)

Systemic RV n (%) 17 (16) 9 (15) 27 (29)

Increase RVEF (%) 13+11* Median: 14 7*

Decrease QRS (ms) 38+29* Median: 15 Median: 21


Increase RVEF n (%) n/a n/a n/a

NYHA improvement ≥1 class n (%) 13 (76) n/a n/a

RVEF increase or NYHA improvement n (%) n/a 2 (22) 19 (70)

Single ventricle n (%) 7 (7) 13 (22) 4 (4)

Increase LVEF or RVEF (%) 7.3+5.7 median: 10 n/a

Decrease QRS (ms) 45+26* median: 13 n/a


LVEF or RVEF increase n (%) n/a 10 (77) n/a

NYHA improvement ≥1 class n (%) 2 (30) 7 (54) 2 (50)

RVEF/LVEF increase or NYHA improvement n (%) n/a n/a 3 (75)

Response rates after CRT in three retrospective studies in CHD and paediatric populations, displayed for every anatomical subgroup. Response percentages are on an intention totreat basis, i.e. including the total amount of patients enrolled in the study, regardless of deaths, follow-up, and unsuccessful implantations.LVEF, left ventricular ejection fraction; NYHA, New York Heart Association class; RVEF, right ventricular ejection fraction.*Statistical difference (P , 0.05) when compared with data before CRT implantation.aPatients with concurrent cardiac surgical procedure excluded.


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of 22%, whereas Janousek et al.16 observed improvement in 70% ofpatients with a systemic RV.

Single-ventricle patients constituted 4–22% of the cohorts(Table 2). Improvement in NYHA functional class was observedin 30–54% of these patients.14– 16 In addition, Janousek et al.16

observed an echocardiographic or clinical response in 75% ofthe patients of this subgroup.

Finally, 55–77% of patients in the three studies on CRT had apacemaker before up-grading to CRT.14– 16 In the study of Janou-sek et al.16, the patients with failure of the systemic LV whowere upgraded from single-site pacing to biventricular pacingshowed the highest response rate. In addition, these patientsshowed a significantly larger improvement in NYHA functionalclass and a larger extent of LV reverse remodelling when com-pared with the rest of the study population.

On the basis of this clinical evidence, CRT may be a promisingtherapy to improve cardiac performance and clinical outcome ofCHD and paediatric patients with heart failure. However, severalissues need further investigation. First, the median follow-up dur-ation of the three trials described is limited (4.8–8.4 months;Table 1). Additional trials reporting on the long-term effects ofCRT in CHD and paediatric patients are warranted. Furthermore,comparisons of the CRT response rate between heart failure adultpatients and CHD and paediatric patients should take into con-sideration patient age and size-related differences. Finally, currentselection criteria remain controversial in CHD and paediatricpatients, and accurate selection of patient subgroups that willbenefit from CRT is warranted.

Selection of congenital heart disease andpaediatric patients for cardiacresynchronization therapyCurrent inclusion criteria for CRT in the adult populations are:NYHA functional class III or IV despite optimal pharmacologicaltherapy, LVEF , 35% and QRS duration .120 ms.8,9 However,the majority of the studies on CRT in CHD and paediatric popu-lations have not applied these criteria prospectively.

NYHA functional class III or IV despite optimal pharmacologicaltherapy is one of the inclusion criteria. In CRT trials enrolling CHDand paediatric populations, the majority of patients were in NYHAfunctional class I or II, indicating only mild heart failure. This discre-pancy with the current guidelines likely resulted from a substantialproportion of CHD and paediatric patients with a concomitantindication for cardiac surgery (15–32%), ICD implantation or anti-bradycardia pacing (55–77%).14– 16 These concomitant indicationsmay well have accelerated decision-making on CRT implantationduring the same procedure in patients with only mild heartfailure. In addition, Janousek et al.16 demonstrated that NYHAfunctional class is a strong determinant of CRT response inCHD and paediatric patients, with a higher favourable responserate in those patients with NYHA functional class I– II than inpatients in NYHA functional class III– IV. Indeed, the benefits ofCRT in adult patients with mild symptomatic heart failure havebeen evaluated. The REsynchronization reVErses Remodeling inSystolic left vEntricular dysfunction (REVERSE) trial included over600 heart failure patients in NYHA functional class I– II undergoing

CRT implantation.42 After 1 year follow-up, reverse LV remodel-ling and improved LVEF was observed, indicating a beneficialeffect of CRT even with mild clinical heart failure. Therefore, theimplantation of CRT at an early stage may help to prevent the pro-gression and/or the development of heart failure. However, whenCRT is considered in asymptomatic or mildly symptomaticpatients, the possible effects of implantation of a device onquality of life need to be weighed against the benefits of CRT oncardiac performance. Importantly, in young paediatric patients,grading of heart failure by NYHA class may not be reliable.43,44

In those patients, careful monitoring of ventricular performanceby measuring ejection fraction may yield more reliable dataabout response to CRT.

Another inclusion criterion is LVEF , 35%. The mean value ofsystemic ventricular ejection fraction in the three CHD and paedia-tric cohorts varied between 26 and 36%. Dubin et al.15 observed alower baseline ejection fraction of the systemic ventricle in non-responders (24+11 vs. 32+14%, P ¼ 0.04). However, evalu-ation of this parameter in the CHD and paediatric population ishampered by methodological difficulties. Although echocardio-graphic LVEF is reliable in patients with a systemic LV,45 in patientswith RV failure (systemic RV or single RV), standard echocardiogra-phy is less accurate for quantifying RV volumes and ejection frac-tion due to the complex RV geometry. In this regard,quantification with magnetic resonance imaging is currently pre-ferred over echocardiography since this imaging tool does notrely on geometrical assumptions.46,47 Nevertheless, the majorityof the CRT devices currently implanted are not compatible withmagnetic resonance scanners and therefore, patient follow-upwith this imaging technique is not feasible after device implantation.

Finally, CRT is indicated in patients with wide QRS complex.Current guidelines include width of the QRS complex .120 ms

Figure 2 Atrioventricular dyssynchrony. Example of a paedia-tric patient with idiopathic dilated cardiomyopathy and atrioven-tricular dyssynchrony as assessed with pulsed wave Dopplerechocardiography. Left ventricular filling time is reduced(,40% of RR interval) and the early (E-wave) and late(A-wave) diastolic inflow waves are fused. LV, left ventricle.


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as a marker of electrical dyssynchrony. However, it has beenshown that the relationship between electrical conduction delayand mechanical dyssynchrony is not straightforward.2 – 6 In addition,the value of QRS complex duration to predict response to CRTmay be suboptimal with a sensitivity and specificity of 54%.48

The mean QRS duration in the three retrospective CHD and pae-diatric cohorts described above was .120 ms.14–16 However,Dubin et al. stated that only 54% of included patients met the com-bined criteria of QRS . 120 ms and systemic ventricle ejectionfraction ,35%. In addition, Pham et al.49 evaluated the effects ofbiventricular pacing in 19 CHD patients with a narrow QRScomplex (96+ 18 ms). Temporary epicardial leads wereimplanted and several pacing modes, including biventricularpacing, were tested for 10 min each. Compared with conventionalpacing modalities, biventricular pacing was associated with signifi-cant improvements in cardiac index in these patients withnarrow QRS complex. Furthermore, various imaging studies inpaediatric patients with dilated cardiomyopathy have demon-strated the presence of LV mechanical dyssynchrony despitenarrow QRS complex.50 –52 These findings indicate that paediatricpatients may benefit from CRT, even in the presence of a narrowQRS complex. Indeed, several adult trials included heart failurepatients with narrow QRS complex and LV mechanical dyssyn-chrony, and observed favourable outcomes after CRT.53,54

As mentioned above, important differences with the currentCRT inclusion criteria are observed in the paediatric cohorts,especially with regard to clinical heart failure classification andQRS duration. Moreover, the anatomical substrate may constitutean additional issue to be considered before CRT implantation inthese populations. Cardiac imaging of ventricular function andmechanics (dyssynchrony) may provide additional insight into theeffects of CRT and improve selection of CHD and paediatricpatients who will benefit from CRT.

Echocardiographic assessment ofcardiac dyssynchronyAs mentioned before, prolonged QRS duration is the only cri-terion considered by current guidelines defining the presence ofcardiac dyssynchrony. However, QRS duration might not be

Figure 3 Inter-ventricular dyssynchrony. Example of inter-ventricular dyssynchrony in a patient with congenital atrioventri-cular block and chronic right ventricular pacing. Inter-ventriculardyssynchrony can be evaluated with pulsed wave Doppler echo-cardiography. The time from onset of the QRS complex to theonset of flow (pre-ejection interval) is measured in the pulmon-ary artery and in the left ventricular outflow tract. The differencebetween both pre-ejection times yields the so-called inter-ventricular mechanical delay (IVMD). In this example, the IVMDis 45 ms (.40 ms6). Ao, aorta; Pulm, pulmonary artery.

Figure 4 Left ventricular dyssynchrony: M-mode septal-to-pos-terior wall motion delay. Example of left ventricular dyssynchronyin a patient with a truncus arteriosus after aortic and pulmonaryvalve replacement. The patient shows flattening of the septum inthe parasternal short-axis view due to right ventricular outflowobstruction. Left ventricular dyssynchrony is measured withM-mode septal-to-posterior wall motion delay (SPWMD). Fromthe parasternal short-axis M-mode recording of the left ventricle,a delay of 240 ms is observed between the peak systolic inwardmotion of the septum and the peak systolic inward motion of theposterior wall (SPWMD ≥ 130 ms indicates left ventriculardyssynchrony59).


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accurate enough to identify those patients who will benefit fromCRT.17 It has been demonstrated that the presence of mechanicaldyssynchrony, rather than electrical dyssynchrony, may be a morerobust parameter to select patients who will benefit from CRT.17

Mechanical dyssynchrony may occur at different levels (atrioventri-cular, inter-ventricular and intra-ventricular55) and can be assessedwith various cardiac imaging techniques. Echocardiography is themainstay imaging modality to evaluate cardiac dyssynchrony andpermits comprehensive assessment of these three different typesof dyssynchrony.

Atrioventricular dyssynchronyAtrioventricular dyssynchrony refers to a prolonged delay in atrio-ventricular sequential contraction, resulting from prolongation ofthe PR interval, QRS widening, or both.56 With the use of pulsed-wave Doppler echocardiography, atrioventricular dyssynchronycan be assessed by measuring LV filling time from transmitralflow recordings. When the atrioventricular delay is prolonged,the early (E-wave) and late (A-wave) diastolic waves fuse and dias-tolic filling time of the ventricles is shortened.56 In adult patients, aLV filling time/RR interval ,40% indicates atrioventricular dyssyn-chrony (Figure 2).56 In CHD and paediatric patients with LV sys-temic failure, no data on LV filling time are available so far.Nevertheless, surgical or congenital atrioventricular block maycause atrioventricular dyssynchrony and therefore the thresholdof LV filling time/RR interval ,40% needs investigation.However, in CHD patients with systemic RV failure, one smallstudy provided data on RV filling time. Janousek et al.29 assessedRV filling time before and after CRT in eight patients with systemicRV failure and right bundle branch block. Right ventricle filling timewas calculated from the transtricuspid pulsed-wave Doppler spec-tral signal. At 17 months follow-up, RV filling time (normalized for

RR interval) had increased from 45.1+6.5 to 50.0+ 6.1% (P ,

0.01).

Inter-ventricular dyssynchronyInter-ventricular dyssynchrony refers to contraction delay betweenthe RV and the LV. Several indexes have been proposed to assessthis type of cardiac dyssynchrony. One of the first was the inter-ventricular mechanical delay (IVMD) assessed with pulsed-waveDoppler echocardiography. Inter-ventricular mechanical delay isobtained by calculating the difference between aortic and pulmon-ary pre-ejection intervals (the time from the onset of QRS to theonset of flow; Figure 3). An IVMD . 40 ms indicates inter-ventricular dyssynchrony.6,56 The CARE-HF trial demonstratedthe use of this index to predict response to CRT. Differencesbetween CHD patients and adult heart failure patients mayaccount for different IVMD cut-off values. For example, in patientswith transposition of the great arteries (with normal LVEF), theaortic and pulmonary pre-ejection intervals differ from healthyindividuals.57 Furthermore, in patients with pulmonary stenosis,the pulmonary pre-ejection interval may be prolonged.58 Little isknown about IVMD cut-off values predicting response to CRT inpaediatric and CHD patients.24,29,31,39 The available studiesincluded too few patients precluding to draw robust conclusionsregarding the performance of this dyssynchrony index to predictresponse to CRT. However, a consistent reduction in IVMDafter CRT was reported in the majority of patients.24,29,31,39

Intra-ventricular dyssynchrony:left ventricleIntra-ventricular dyssynchrony of the LV (LV dyssynchrony) hasshown to be an independent determinant of response to CRT

Figure 5 Left ventricular dyssynchrony: colour-coded TDI septal-to-lateral wall motion delay. Left panel: Example of a patient with tricuspidatresia after Fontan procedure, with septal-to-lateral wall motion delay. Apical ‘four-chamber’ view assessed with TDI. Two regions of interestare placed off-line at the basal septum (yellow) and left ventricular lateral wall (blue). Right panel: Time–velocity curves are reconstructed. Thetime difference between peak systolic velocity of the septal and lateral segments (septal-to-lateral wall motion delay) is 75 ms in this patient(.60 ms62). SLWMD, septal-to-lateral wall motion delay; TDI, tissue Doppler imaging.


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and long-term survival in adult patients with heart failure. Theassessment of LV dyssynchrony can be performed with variousmethods, evaluating time between mechanical events of two ormore LV segments. Pitzalis et al.59 introduced the use ofM-mode echocardiography to assess LV dyssynchrony. From theparasternal short-axis view of the LV, the time differencebetween the maximal systolic inward motion of the septal and pos-terior wall was calculated: the so-called septal-to-posterior wallmotion delay (SPWMD) (Figure 4). A cut-off value of SPWMD of≥130 ms was proposed to predict response to CRT. In theCHD paediatric population several case reports and two smalltrials have used this index to evaluate the effects ofCRT.24,39,41,60,61 For example, Tomaske and colleagues describedsix children with CHD and systemic LV failure who were treatedwith CRT.24 In these patients, SPWMD decreased from 312+24 to 95+57 ms (P ¼ 0.03) after one month follow-up, along

with an improved LVEF (from 41+6 to 53+8%, P ¼ 0.03) anda trend towards a decreased LV end-diastolic volume (from70+22 to 63+18 mL/m2, P ¼ 0.09).

The advent of TDI, measuring regional myocardial velocities, hasprovided useful parameters to assess LV dyssynchrony, identifyingresponders to CRT with high specificity and sensitivity.17 Bothpulsed-wave TDI and colour-coded TDI can be used to assessLV dyssynchrony. Unlike pulsed-wave TDI, colour-coded TDI canprovide myocardial velocity tracings of two or more segments sim-ultaneously (Figure 5). The feasibility and accuracy of colour-codedTDI to evaluate LV dyssynchrony have been extensively exploredin studies on CRT in the adult population.17,62– 64 One of thefirst indices was the time difference between peak systolic vel-ocities of the septal and the lateral LV wall. From the apical4-chamber view, the time difference between peak systolic velocityof the basal septal and basal lateral walls was calculated: the

Figure 6 Left ventricular dyssynchrony: TDI-derived radial and longitudinal strain. (A) Example of a post-operative tetralogy of Fallot patientwith right ventricular dilatation and left ventricular dyssynchrony, assessed with TDI-derived radial strain. Left: Regions of interest are placed atthe septal (blue) and posterior (yellow) wall of the left ventricle. Right: Radial strain (thickening of myocardium) curve. Dyssynchrony can bequantified by measuring time between peak radial strain at the septal and posterior walls (white arrow). A delay between the septal and pos-terior wall .130 ms indicates radial dyssynchrony.65 (B) Example of a patient with left ventricular dyssynchrony, assessed with TDI-derivedlongitudinal strain. Left: Regions of interest are placed at the inferior (yellow) and anterior wall (blue). Right: Longitudinal strain (shorteningof myocardium) curve. Dyssynchrony can be quantified by measuring time between peak radial strain at the septal and posterior walls(white arrow).66 TDI, tissue Doppler imaging.


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so-called septal-to-lateral wall delay.62 A septal-to-lateral walldelay ≥60 ms predicted response to CRT with a sensitivity of76% and a specificity of 78%.62 Subsequently, a 4-segmentmodel, including the basal segments of the septal, lateral, inferiorand anterior walls was evaluated.63 The maximum delay betweenpeak systolic velocities among the four LV walls was calculated.A delay ≥65 ms predicted clinical and echocardiographic responseto CRT with high sensitivity (92%) and specificity (92%).63 Finally,Yu et al. proposed a 12-segment model, evaluating time to peaksystolic velocity at six basal and six mid-myocardial segments ofthe LV.64 A standard deviation ≥32.6 ms predicted LV reverseremodelling after CRT with a sensitivity and specificity of 100%.

In paediatric populations, the usefulness of these indices hasbeen demonstrated in several case reports and one smalltrial.19,20,24 Tomaske et al. applied a 4-segment TDI model in sixCHD patients with systemic LV failure.24 At baseline, themaximum intra-LV delay between two basal and two mid-ventricular LV segments in the apical four-chamber view was64+10 ms and improved to 37+8 ms after 1 month of CRT(P ¼ 0.03), along with an improved LV systolic performance.

In addition to myocardial velocity, myocardial strain can beobtained from colour-coded TDI images (Figure 6). The advantageof strain imaging over myocardial velocity imaging is that strain indi-cates active myocardial deformation or contraction whereas vel-ocity represents passive motion or displacement. Differences intime to peak strain can be calculated to quantify LV dyssyn-chrony.65,66 TDI-derived strain has been evaluated in a paediatricstudy.67 Abd El Rahman et al.67 assessed TDI-derived longitudinal

strain in 25 patients (median 19 years, range: 3–35 years) with tet-ralogy of Fallot and in 25 age-matched controls. The mean time topeak strain was assessed at the LV free wall (basal, mid and apical)as well as at the septum, and the mean septal-to-LV free wall timedelay was calculated. Left ventricular dyssynchrony was defined asa septal-to-LV free wall delay two standard deviations above themean observed in controls (.25.8 ms). Accordingly, 52% of tetral-ogy of Fallot patients showed LV dyssynchrony. These patients hadlonger QRS duration (155+19 vs. 136+23 ms, P ¼ 0.018) andan impaired LV performance compared with patients without dys-synchrony, as assessed with the Tei index (Tei index in patientswith LV dyssynchrony: 0.5+0.08, Tei index in patients withoutLV dyssynchrony: 0.38+ 0.06, P ¼ 0.004).

Finally, the advent of novel echocardiographic techniques,including 2D strain and RT3DE has enabled assessment of dyssyn-chrony by evaluating active myocardial deformation (2D strain) orby evaluation of volumetric changes in a three-dimensional fashion(RT3DE).

Two-dimensional strain imaging or speckle-tracking strainimaging is a novel echocardiographic technique that permits multi-directional and angle-independent assessment of LV deformation.With this technique, the so-called speckles (natural acousticmarkers equally distributed within the myocardium in 2D grey-scale images) are tracked frame-by-frame throughout the cardiaccycle. The change of their position relative to their original positionis used to calculate myocardial strain. Left ventricular dyssynchronycan be characterized by evaluating radial strain (thickening ofthe myocardium in the short-axis views) (Figure 7). At the

Figure 7 Left ventricular dyssynchrony: two-dimensional speckle tracking. Example of a post-operative patient with atrioventricular septumdefect and left ventricular dyssynchrony as assessed with two-dimensional speckle-tracking radial strain. Left panel: A region of interest can beindicated in a two-dimensional grey-scale image. The colours of the region of interest correspond with the colours of the time–strain curves inthe right panel. Right panel: Time–radial strain curves of the different segments of the left ventricle. The time delay in peak radial strain betweenthe antero-septal (yellow) and the posterior segments (purple curve) is 315 ms (≥130 ms), indicating the presence of significant left ventriculardysynchrony.69,68


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mid-ventricular short-axis view of the LV, a maximum difference of≥130 ms in time to peak strain between the antero-septal and theposterior LV segments has shown to predict favourable responseto CRT in adult populations.68,69 Other adult series have evaluatedthe use of circumferential (LV shortening along the short-axis cur-vature of the LV) and longitudinal strain to measure LV dyssyn-chrony and to evaluate the effects of CRT.70,71 Tomaske et al.24

investigated LV dyssynchrony by assessing 2D circumferentialstrain in six CHD patients who underwent CRT for systemic LVfailure. The maximum difference between the earliest and thelatest activated segments and the standard deviation of time topeak strain of 12 segments were calculated at baseline and at 1month follow-up. Both dyssynchrony parameters decreased signifi-cantly at 1 month follow-up after CRT (maximum differencedecreased from 201+ 35 to 99+23 ms, P ¼ 0.03; the standarddeviation decreased from 72+14 to 40+ 15 ms; P ¼ 0.03).Along with the mechanical resynchronization, the LVEF improved

significantly at 1 month follow-up (from 41+6 to 53+ 8%, P ¼0.03).24 In addition, 2D strain imaging permits evaluation of thelatest activated areas where the LV pacing lead should ideally beplaced. In adult populations, the position of the LV pacing lead con-cordant with the latest activated segment has demonstrated to bea determinant of positive response to CRT and superior long-termoutcome.72 In CHD and paediatric studies, the usefulness of thistechnique to identify the latest activated segment and to guidethe LV lead placement has been also demonstrated.73,74

Finally RT3DE provides regional time–volume curves for theevaluation of LV dyssynchrony (Figure 8). Left ventricular dyssyn-chrony is assessed by calculating the systolic dyssynchrony index(SDI). The standard deviation of time to minimum systolicvolume of 16 LV segments is calculated. Marsan et al.75 demon-strated that a SDI cut-off value of 6.4% predicted long-term CRTresponse with high sensitivity (88%) and specificity (85%).Concerning CHD patients, Bacha et al.34 performed RT3DE in

Figure 8 Left ventricular dyssynchrony assessed with real-time three-dimensional echocardiography. Example of a post-operative tetralogy ofFallot patient with left ventricular dyssynchrony, as assessed with real-time three-dimensional echocardiography. Contours are drawn at end-systole (A) and end-diastole in the short-axis view, four-chamber view, two-chamber view, and long-axis view. An automated tracking algorithmtraces the myocardium throughout the cardiac cycle. The time–volume curves (C) are displayed, depicting instantaneous volume of each of theleft ventricular segments (B), from which a systolic dyssynchrony index (standard deviation of time to minimum systolic volume of left ventri-cular segments) can be calculated. In this example, the systolic dyssynchrony index is 6.6%. A systolic dyssynchrony index .6.4% indicates leftventricular dyssynchrony.75 SDI, systolic dyssynchrony index.


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10 single-ventricle patients who received multisite pacing post-operatively. At 48 h after CRT, the SDI of the single-ventricledecreased significantly (from 10.3+4.8 to 6.0+1.4%, P , 0.05).

The proposed inter-ventricular dyssynchrony parameters in theadult trials resemble the observations on LV dyssynchrony in pae-diatric and CHD patients. However, the predictive value of inter-ventricular dyssynchrony of the LV in CHD and paediatric patientsmay vary in the various anatomical subgroups. Furthermore,several factors such as previous pacing strategies, the presenceand location of scar tissue and haemodynamic abnormalities mayinfluence the CRT response.76 Additional trials are needed toestablish cut-off values of LV dyssynchrony in CHD and paediatricpatients, taking into consideration the various anatomicalsubgroups.

Intra-ventricular dyssynchrony:right ventricleSimilar to the assessment of intra-ventricular dyssynchrony of theLV in the adult population, intra-ventricular dyssynchrony of theRV has been studied in CHD patients with systemic RV failure.Van de Veire et al.33 assessed septal-to-lateral delay within theRV in the apical four-chamber view with colour-coded TDI in apatient with RV-systemic failure who was upgraded from conven-tional pacing to CRT. After 2 weeks, the RV septal-to-lateraldelay decreased from 80 ms to completely synchronous contrac-tion and exercise capacity improved significantly. In addition, Janou-sek et al.29 evaluated intra-ventricular dyssynchrony of the RV withTDI-derived strain before and after CRT in eight patients with RVsystemic failure. Right ventricle dyssynchrony was quantified bymeasuring the largest delay in time to peak strain between fourmid-ventricular RV segments (septal, lateral, anterior, and pos-terior). After 4 days of CRT, RV dyssynchrony significantlyreduced (from 138+ 59 to 64+21 ms, P ¼ 0.042). In addition,RVEF, as assessed with radionuclide angiography at 4 monthsfollow-up, improved from 41.5 to 45.5% (P , 0.01).

According to these data, assessment of intra-ventricular dyssyn-chrony of the RV could be useful in selecting patients with RVfailure for CRT. However, unlike LV dyssynchrony assessment,characterization of RV dyssynchrony has been less explored,77–

79 and additional studies evaluating RV dyssynchrony are neededto determine its value for predicting success of CRT in RV failure.

Conclusion and future perspectiveThe beneficial effects of CRT on clinical outcomes and LV functionof adult heart failure patients has encouraged the use of thistherapy in other populations, such as CHD and paediatricpatients.14– 16 The population with CHD is growing, and this sub-group of patients has a high prevalence of heart failure during latefollow-up.11 Although some studies have demonstrated the ben-eficial effects of CRT in CHD and paediatric patients, there areseveral concerns. First, the population of CHD and paediatricpatients included in the studies is highly heterogeneous, comprisingvarious anatomical substrates (systemic LV, systemic RV, single ven-tricle) and aetiologies of heart failure (chronic single-site ventricu-lar pacing).14–16 Furthermore, heterogeneity in this population

results from patient age and size variations. Second, the currentadult selection criteria may not be suitable for the CHD and pae-diatric heart failure population. Only a minority of CHD and pae-diatric patients included in studies on CRT fulfilled the adultguidelines of QRS . 120 ms, NYHA functional class III or IV andLVEF , 35%.14– 16 Third, the various anatomical substrates mayresult in patterns of cardiac dyssynchrony that may not be accu-rately characterized with ECG criteria. The study of mechanicaldyssynchrony with various imaging modalities may provide amore accurate definition of cardiac dyssynchrony and improveselection of those CHD and paediatric patients who have thehighest likelihood of response to CRT. However, the feasibilityand performance of the various dyssynchrony parameters inCHD and paediatric patients may differ from those observed inadult heart failure patients.

In conclusion, CRT may be a promising therapy to improve theclinical outcome of CHD and paediatric patients with heart failure.However, more studies are needed to establish appropriate guide-lines for patient selection, taking into account the different anatom-ical subgroups.

FundingA.E.H. has received a grant from the Willem-Alexander Kinder Fonds,Leiden, The Netherlands. A.A.W.R. is supported by a grant of theNetherlands Heart Foundation (2008T81).

Conflict of interest: J.J.B. has received grants from Biotronik (Berlin,Germany), Medtronic (Minneapolis, MN, USA), Boston Scientific Cor-poration (Natick, MA, USA), Lantheus Medical Imaging (N. Billerica,MA, USA), St Jude Medical (St Paul, MN, USA), GE Healthcare(Milwaukee, WI, USA), and Edwards Lifesciences (Irvine, CA, USA).M.J.S. has received grants from Biotronik (Berlin, Germany), Medtronic(Minneapolis, MN), Boston Scientific Corporation (Natick, MA).

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