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QRS Duration and Mechanical DyssynchronyCorrelations with Right Ventricular Function

after Fontan Procedure

Janaki Gokhale, MD, Nazia Husain, MD, MPH, Lisa Nicholson, PhD, Karen M. Texter, MD,Ali N. Zaidi, MD, and Clifford L. Cua, MD, Columbus, Ohio

Background: In studies of adult patients, increased QRS duration and mechanical dyssynchrony have beenassociated with decreased ventricular function. The aim of this study was to test the hypothesis that similarfindings would be present in a population of patients with hypoplastic left heart syndrome (HLHS) after theFontan procedure.

Methods: A retrospective cross-sectional study was conducted. All patients with HLHS after the Fontan pro-cedure were eligible. QRS duration was measured using 12-lead electrocardiography. Echocardiographicmeasurements of mechanical dyssynchrony included Doppler tissue imaging (DTI) QRS to onset of s0 wavedifference between the left ventricle and the right ventricle, time to peak strain, time to peak systolic strainrate (SRs), the standard deviation of time to peak strain rate (modified Yu strain), and the standard deviationof time to peak SRs (modified Yu SRs). Right ventricular (RV) functional measurements included DTI s0 wave,DTI RV myocardial performance index, global strain, global SRs, and RV fractional area change. Pearson’scorrelations were performed between the variables.

Results: Thirty-one echocardiographic studies were performed on 26 patients. The median age was 5.3 years(range, 2.5–15.4 years). QRS duration was correlated significantly with global SRs (r = 0.42). Time to peak SRswas correlated significantly with DTI s0 wave (r = �0.48) and global SRs (r = 0.37). Modified Yu SRs was cor-related significantly with global strain (r = 0.35) and RV fractional area change (r = �0.35).

Conclusions: Both QRS duration and mechanical dyssynchrony were correlated with RV function, albeitweakly. The clinical significance of these findings is intriguing, but only larger studies will determine if thesemeasurements are reliable in guiding treatment options for this complex patient population. (J Am Soc Echo-cardiogr 2012;-:---.)

Keywords: Hypoplastic left heart syndrome, Fontan, Strain, Dyssynchrony, Echocardiography

Because of surgical andmedical advances, life expectancy is increasingfor patients with hypoplastic left heart syndrome (HLHS). A major is-sue these patients face as they age is progressive heart failure, with a re-ported incidence as high as 40%.1,2 One treatment that has beenestablished to improve morbidity and mortality in the adult heartfailure population is cardiac resynchronization therapy (CRT).3,4

One criterion used to determine if CRT is an appropriate treatmentoption is QRS duration.5,6 Various mechanical dyssynchronymeasurements, measured via echocardiographic techniques, havealso been used to determine if patients would respond to CRT, butresults have been mixed.7-9

CRT has been used in the congenital heart population for heart fail-ure as well, but indications are usually determined on a case-by-case

rt Center, Nationwide Children’s Hospital, Columbus, Ohio.

sts: Janaki Gokhale, MD, The Heart Center, Nationwide Children’s

Children’s Drive, Columbus, OH 43205 (E-mail: janakig@gmail.com).

6.00

2 by the American Society of Echocardiography.

rg/10.1016/j.echo.2012.10.018

basis.10-12 Increased QRS duration in patients with HLHS comparedwith historical controls with normal hearts has been previouslynoted.13 In addition, increased mechanical dyssynchrony via echocar-diographic evaluation has been documented in patients with singleright ventricles.14-18 The relationship of QRS duration andmechanical dyssynchrony to right ventricular (RV) function, however,has not been clearly defined in patients with single RV physiology.

We hypothesized that QRS duration andmechanical dyssynchronymeasurements in patients with HLHS after the Fontan procedurewould correlate with measurements of ventricular function, similarto findings in adult studies.

METHODS

The institutional review board approved this cross-sectional, retro-spective study. All patients with HLHS who had undergone theFontan procedure were included. Patients also needed to haveadequate echocardiographic images with frame rates of 60 to110 frames/sec performed obtained using a Vivid I or Vivid 7machine(GE Healthcare, Wauwatosa, WI). An electrocardiogram obtainedwithin 3months of the echocardiogramwas also required. The offline

1

Abbreviations

cMRI = Cardiac magneticresonance imaging

CRT = Cardiacresynchronization therapy

DTI = Doppler tissue imaging

HLHS =Hypoplastic left heartsyndrome

ICC = Intraclass correlationcoefficient

MPI = Myocardial

performance index

RV = Right ventricular

SRs = Systolic strain rate

2 Gokhale et al Journal of the American Society of Echocardiography- 2012

echocardiographic database wassearched for these specific pa-tients. Patients needed to be instable sinus rhythm or in anatrial-derived rhythm. Patientswhose intrinsic rhythm lackedatrioventricular synchrony andpatients who had ventricularpaced rhythms were excluded.Baseline demographics includedage, weight, cardiac diagnosis,previous surgeries, and oxygensaturation on room air.

Figure 1 Apical four-chamber view of single right ventricle (RV).IVS, Interventricular septum; rLV, rudimentary left ventricle.

Electrocardiography

Rhythm and QRS duration weredetermined on 12-lead electro-cardiography. QRS duration was

measured in lead V1 for consistency by a single observer (C.L.C.)blinded to clinical and echocardiographic data. Measurements weremade offline using the Muse system (GE Healthcare).

Figure 2 DTI measurements.

Echocardiography

All echocardiographic studies were performed on a Vivid I or Vivid 7machine. All measurements were made in triplicate by a singleobserver (J.G.). Although the observer whomeasured the echocardio-graphic variables could in fact see the electrocardiographic tracingswhile obtaining the echocardiographic measurements, the observerdid not measure or have knowledge of QRS width. Postprocessingof all images was completed offline using EchoPAC version 7 (GEHealthcare).

Standard Echocardiography

Views equivalent to an apical four-chamber view were obtained(Figure 1). Images were optimized for the visualization of the epicar-dial and endocardial borders of the single right ventricle. RV fractionalarea change ([RV diastolic area � RV systolic area]/RV diastolic area)was obtained per published guidelines.19

Doppler Tissue Imaging (DTI) Measurements

Spectral DTI measurements of the right free wall and left free wall atthe level of the atrioventricular valve annulus were obtained in theapical four-chamber view. DTI peak systolic annular velocity (s0) ofthe RV free wall was measured as one marker of RV function. Themyocardial performance index (MPI) was calculated ([isovolumetriccontraction time + isovolumetric relaxation time]/ejection time) forthe right ventricle from the DTI values as another marker of RV func-tion (Figure 2).19

QRS onset to the onset of the s0 wave was measured from DTIimages of the free walls using a simultaneous electrocardiogram.The absolute difference between the RV and left ventricular freewall intervals was determined and used as a marker of mechanicaldyssynchrony.15

Strain Measurements

The endocardial border of the single right ventricle in an apical four-chamber view was traced from the septal-atrioventricular annularhinge point to the apical septum and then to the RV lateral wall at

the lateral-atrioventricular annular hinge point. The automatedepicardial-to-endocardial computer-generated border, or region of in-terest, was adjusted to include the epicardium. The borders were ac-cepted only if visual inspection showed adequate tracking and if thesoftware indicated adequate tracking for all segments (green). Patientswhose segments did not track well because of artifacts or inadequatevisualization of the lateral borders of the right ventricle were ex-cluded. Measurements of global RV strain and global RV systolicstrain rate (SRs) were obtained as markers for RV function (Figure 3).

QRS onset to time to peak strain and SRs was measured for all sixsegments. The standard deviations of the time to peak strain and thetime to peak SRs were then calculated to give modified Yu indices forstrain and SRs, respectively. QRS onset to time to peak global strainand global SRs was also obtained as other values for mechanicaldyssynchrony.14,16,20

Correlations

RV fractional area change, RV free wall DTI s0 wave, RV MPI, RVglobal strain, and RV global SRs were used as measurements of RVfunction. QRS duration was used as a marker of electrical dyssyn-chrony. QRS onset to s0 wave difference between the RV and leftventricular free walls, QRS onset to time to peak global strain andSRs, modified Yu strain, and modified Yu strain rate were used asvalues for mechanical dyssynchrony.

Pearson’s correlations were performed between RV function mea-surements and QRS duration as well as RV function measurementsand RV mechanical dyssynchrony values. P values #.05 wereconsidered significant. To examine interobserver and intraobservervariability, three measurements were taken for each parameter on

Figure 3 Two-dimensional strain analysis of a patient with single right ventricle. Segments are color coded as follows: yellow = basalinterventricular septum, light blue =mid interventricular septum, green = apical interventricular septum, red = basal RV free wall, darkblue = mid RV free wall, purple = apical RV free wall. (Top left) Strain curve with global RV strain value. (Bottom left) Segmental strainvalues. (Top right) Color-coded segmental and global RV strain curves. Dashed white line = global strain curve. (Bottom right) CurvedM-mode. GS, Global strain.

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a random sample of 10 subjects and completed by one observer. Anadditional observer completed a single set of measurements on thesame 10 subjects on all parameters. Intraclass correlation coefficients(ICCs) were used to measure the levels of intraobserver and interob-server variability. Agreement was considered excellent (>0.75), good(0.60–0.74), or poor (<0.40) as defined by the ICC. All statisticalanalyses were performed using SAS version 9.2 (SAS Institute, Inc.,Cary, NC).

RESULTS

A total of 30 patients with HLHS were identified, with 35 studiesperformed. Four studies were excluded, one because of an atrial ar-rhythmia, one because of the lack of an electrocardiographic tracingat the time of imaging, and two because of inadequate imagingand/or speckle-tracking analysis. A total of 31 studies from 26 patientswere thus available for analysis.

The median age of the patients at the time of echocardiographywas 5.3 years (range, 2.5–15.4 years), the median time fromFontan procedure was 38.7 months (range, 2.8–134.3 months), themedian weight was 10.7 kg (range, 11.2–60.8 kg), and median oxy-gen saturation on room air was 95% (range, 80%–99%). Twenty pa-tients underwent hybrid procedures21 and six patients Norwoodprocedures with modified Blalock-Taussig shunts as their initial surgi-cal procedures. Fifteen patients underwent extracardiac nonfenes-trated Fontan procedures, four underwent extracardiac fenestratedFontan procedures, and seven patients underwent lateral tunnel fen-estrated Fontan procedures as their last surgical cardiac procedures.

The mean QRS duration was 96618 msec. Twenty-two of the 31electrocardiographic studies were performed on the same day as theechocardiographic studies, with the rest performed within 3 monthsof echocardiography.

RV mechanical dyssynchrony measurements are presented inTable 1. RV functional measurements are presented in Table 2.Normative data, previously published in other studies,14,15,22 wereavailable for a few variables and are shown in the far right columnfor comparative purposes in both tables. The normative data arefrom pediatric patient populations with structurally normal hearts.

Correlations between mechanical dyssynchrony variables andQRS duration are shown in Table 3. Two of the five mechanical dys-synchrony measurements had correlations with QRS duration.

Correlations between QRS duration and mechanical dyssyn-chrony values with RV measures of function are highlighted inTable 4. Numerical values in the table represent the significantr values. QRS duration was positively correlated with global SRs.Qualitatively, this means that a longer QRS duration corresponds toless negative strain rate values and, theoretically, decreased RV func-tion. Time to peak global SRs was inversely correlated with DTI s0

wave and positively correlated with global SRs. This suggests that in-creasing mechanical dyssynchrony portends worse RV function.Modified Yu strain rate was positively correlated with strain and neg-atively correlated with fractional area change. There was a weak asso-ciation between the modified Yu strain rate and global SRs that didnot reach significance (r = 0.30, P = .09). Again, this implies that in-creasing mechanical dyssynchrony is associated with worsening RVfunctional measurements. A subset analysis was performed on the22 patients who underwent electrocardiography and echocardiogra-phy on the same day. The correlations for this subset of patients weresimilar to those found in the original group.

Interobserver ICCs were excellent for time to peak global strain,time to peak global strain rate, global strain, and global SRs; goodfor DTI s0 wave and RV MPI; and poor for modified Yu strain rate,modified Yu strain, RV fractional area change, and DTI QRS to onsetof s0 wave difference. Intraobserver ICCs were excellent for time topeak global strain, time to peak global strain rate, global strain, global

Table 1 RV mechanical dyssynchrony measurements

Variable

Fontan study

group

Normative

data

DTI QRS to onset of s0 wavedifference (msec)

28.5 6 48.8 17.7 6 11.815

Time to global peak strain (msec) 355 6 48 320.1 6 28.614

Time to global peak SRs (msec) 195 6 39.4Modified Yu strain (msec) 52.6 6 22.8 21.7 6 7.314

Modified Yu SR (msec) 120 6 53.1

Data are expressed as mean 6 SD.

Table 2 RV functional measurements

Variable

Fontan study

group Normative data

DTI s0 wave for RV free wall (cm/sec) 5.5 6 1.3 13.2 6 0.915

DTI RV free wall MPI 0.4 6 0.1 0.3 6 0.115

Global strain (%) �17.6 6 2.9 �31.3 6 3.114

Global SRs (s�1) �1.08 6 0.2 �2.01 6 0.314

RV fractional area change (%) 30.6 6 4.9 54.6 6 10.522

Data are expressed as mean 6 SD.

Table 3 QRS duration and mechanical dyssynchronycorrelations

Correlation coefficients with QRS duration r P

Time to peak strain 0.42 .02

Time to peak SRs 0.42 .02

Modified Yu strain �0.09 .62

Modified Yu SRs 0.07 .70

DTI QRS to onset of s0 wave difference 0.07 .70

Table 4 RV functional correlations with QRS duration andmechanical dyssynchrony values

Function

Dyssynchrony

DTI s0

wave RV MPI Strain SRs

Fractional

area change

QRS NS NS NS 0.41 NS

DTI QRS to onset of s0

wave differenceNS NS NS NS NS

Time to peak strain NS NS NS NS NSTime to peak SRs �0.48 NS NS 0.37 NS

Modified Yu strain NS NS NS NS NSModified Yu SR NS NS 0.35 NS �0.35

4 Gokhale et al Journal of the American Society of Echocardiography- 2012

SRs, and RV MPI; good for DTI s0 wave and modified Yu strain rate;and poor for modified Yu strain, RV fractional area change, and DTIQRS to onset of s0 wave difference.

DISCUSSION

Increased electrical dyssynchrony measured by QRS duration andmechanical dyssynchrony measured via various echocardiographictechniques have been shown in the adult population to correlatewith worse left ventricular and RV function.8,9,23 In the pediatricpopulation with biventricular physiology, narrowing of the QRSduration via CRT has been noted to correlate with improvedfunction.10-12 Increased QRS duration and mechanicaldyssynchrony have been reported in patients with single RVphysiology,13-16 but the correlation with RV function has not beenclearly delineated. In this study, both QRS duration and mechanicaldyssynchrony were correlated with echocardiographic values of RVfunction, albeit weakly.

QRS duration was correlated significantly with global RV strainrate in this study. This finding may imply that similar to studies ofadults with left ventricular heart failure,5,6 QRS duration could beused as a marker in the decision for possible CRT in patients withsingle right ventricles to help improve function. One study showeda disproportionate increase in QRS duration over time in patientswith HLHS, with more than half the patients having QRSdurations greater than the 98th percentile by the time of theirsuperior cavopulmonary anastomosis.13 There are multiple retrospec-tive studies describing the use of CRT in the pediatric population,with improvements in RV function and subsequent decreases inQRS duration, but the number of patients with single RV physiologywas small, and no explicit correlation was made between QRS dura-tion and RV function.10-12 Another study24 documented a significantnegative correlation between QRS duration and RVejection fraction,

measured on cardiac magnetic resonance imaging (cMRI), in patientswith systemic right ventricles who previously had undergoneMustard or Senning operations. Although this latter study was per-formed in patients with two-ventricular physiology, the right ventriclewas the systemic ventricle, which is similar to the situation in thisstudy.

Taking all this into account, this study’s finding of QRS durationcorrelating with single RV function is plausible. This correlationcould be explained by the theory that as ventricular functionworsens for various reasons, electromechanical uncoupling occurs,and electrical dispersion increases. There are obviously multiple vari-ables that may affect and/or are associated with RV function otherthan QRS duration, and these variables need to be further eluci-dated, but the correlation of QRS duration with RV function in pa-tients with single right ventricles is a finding that has not been clearlystated in the past.

Similar to QRS duration, decreased mechanical dyssynchrony andimproved function after CRT have been shown in the adult popula-tion.25,26 The use of mechanical dyssynchrony as a possible criterionfor CRT is still being debated because of inconsistent prognosticresults.7,8 In addition, the definition used for mechanicaldyssynchrony in the adult population may not necessarily be valid inthe pediatric population.27 Despite these issues, some case reportshave described the use of mechanical dyssynchrony measurementsto aid CRT in pediatric patients.28-31 A few pediatric studies havedocumented increased mechanical dyssynchrony in patients withsingle RV physiology compared with age matched controls.14-16

One other study reported a significant correlation betweenmechanical dyssynchrony measured with strain echocardiographyand ejection fractions on cMRI in patientswith single RVphysiology.20

Akin to the studies noted above, there were correlations of me-chanical dyssynchrony with RV function in this study. We cannot val-idate one measurement over the others at this time. This is analogous

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to the issue found in adult studies in which no single measurement ofmechanical dyssynchrony has gained universal acceptance.7,8 Largerstudies of patients with single right ventricles are undoubtedly neededto determine which measurement of mechanical dyssynchrony maybe the most clinically useful. In our population, it appeared thatstrain rate dyssynchrony values had the most significant correlationswith RV function compared with values obtained on DTI analysis.One possible reason is that DTI values were obtained on only twosegments of the heart, whereas strain rate measurements wereobtained on six segments, thus giving a more global, albeit notcomplete, analysis of the right ventricle. Strain rate variables are lesspreload and afterload dependent and are also not affected bytethering issues compared with DTI values,32 so speckle-trackingmeasurements may indeed bemore sensitive in determiningmechan-ical dyssynchrony values that correlate with function. The importanceof mechanical dyssynchrony in this complex population is still un-clear. It must be stressed that adult criteria for CRT do not use me-chanical dyssynchrony, because of mixed results in the prognosticusefulness of these measurements. It may be that this will also provetrue for the pediatric population and mechanical dyssynchrony maynot be a clinically robust tool, but hopefully these data form a startingpoint for that discussion.

Correlations existed between QRS duration and mechanical dys-synchrony in this study. Again, the best measurement of mechanicaldyssynchrony is yet to be determined, but there does appear to be anassociation between the two concepts of electrical andmechanical ac-tivation in patients with single RV physiology. The correlations, how-ever, were weak, suggesting that there are understandably othervariables that need to be taken into account. The weak correlation be-tween these variables is consistent with adult studies documenting pa-tients who have widened QRS durations and minimal mechanicaldyssynchrony and vice versa.8,9,33

There were several limitations to this study. This study was retro-spective, with the usual inherent limitations associated with sucha study design. Not all of the electrocardiograms were obtained onthe same day as the echocardiograms. A subset analysis, though,did not show any major differences in correlations when patientswho did not undergo same-day electrocardiography were excluded.This was a relatively small sample size. Not all segments of the rightventricle were analyzed, and thus significant correlations may havebeen missed. In addition, only longitudinal values were obtained, sono comment can be made on radial and circumferential componentsof RV function and mechanical dyssynchrony. The clinical relevanceof these correlations remains to be determined. Intraobserver and in-terobserver variability ranged from excellent to poor, with most of thepoor correlations occurring with variables that required calculation.This is a consistent issue, as recently highlighted by a largemulti-institutional study in pediatrics.34 Last, RV function was mea-sured using echocardiographic techniques and not with the currentnoninvasive gold standard of cMRI. However, at least one study hasshown that global longitudinal strain, a value that was measured inthis study, correlates with RV ejection fractions measured on cMRIin patients with single RV physiology.20 In addition, another study re-ported that worse RV global longitudinal strain and strain rate wereassociated with increased adverse events in patients with transposi-tion of the great arteries after the Mustard or Senning operation.35

This latter study was performed in patients with two-ventricular phys-iology, but, as in our patient population, the right ventricle served asthe systemic ventricle. These studies at a minimum imply that at leaststrain and strain rate measurements of the systemic right ventricle arereasonable markers of RV function.

CONCLUSIONS

Both QRS duration and mechanical dyssynchrony measurementswere correlatedwithRV function in patientswith single right ventricles,albeit weakly. The clinical significance of these findings is unknown,and only larger studies will determine if these measurements are ben-eficial or not in deciding treatment options for this complex patientpopulation.

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