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Tricuspid Annular Peak Systolic Velocity (S0) in Childrenand Young Adults with Pulmonary Artery HypertensionSecondary to Congenital Heart Diseases, and in Thosewith Repaired Tetralogy of Fallot: Echocardiography

and MRI Data

Martin Koestenberger, PhD, MD, Bert Nagel, MD, William Ravekes, MD, Alexander Avian, MSc,Bernd Heinzl, MD, Andrea Fandl, MD, Thomas Rehak, MD, Erich Sorantin, MD, Gerhard Cvirn, PhD,

and Andreas Gamillscheg, MD, Graz, Austria; Baltimore, Maryland

Background: Tricuspid annular peak systolic velocity (S0), as an echocardiographic index to assess right ven-tricular (RV) systolic function, has not been investigated thoroughly in children and young adults with repairedtetralogy of Fallot (TOF) and pulmonary artery hypertension secondary to congenital heart disease (PAH-CHD).

Methods: S0 values in patients with TOF (n = 183) and PAH-CHD (n = 55) were compared with those in normalsubjects. S0 values were compared with RV ejection fraction and RV end-diastolic volume index (RVEDVi)determined by magnetic resonance imaging.

Results: S0 values became significantly reduced in PAH-CHD patients after 10.4 years of age and after13.6 years of age in patients with TOF compared with the lower boundary of the 62-SD interval of normalsubjects. Significant positive correlations between S0 and RV ejection fraction were seen in patients withTOF (r = 0.66, P < .001) and those with PAH-CHD (r = 0.82, P < .001). Significant negative correlations betweenS0 and RVEDVi were also seen in patients with repaired TOF (r = �0.29, P = .002) and in those with PAH-CHD(r = –0.59, P < .001).

Conclusions: Although initially preserved, in this prospective study, impaired S0 values with increasing agewere found in patients with repaired TOF and PAH-CHD. Persistent pressure overload in patients withPAH-CHD as well as volume overload in those with repaired TOF might lead to systolic RV functional impair-ment and increased RVEDVi. The validity of S0 data was supported by magnetic resonance imaging data(RVEDVi and RV ejection fraction). (J Am Soc Echocardiogr 2012;-:---.)

Keywords: Tricuspid annular peak systolic velocity, Right ventricular systolic function, Indexed end-diastolicvolume, Magnetic resonance imaging, Pediatric patients, Tetralogy of Fallot, Pulmonary artery hypertensionsecondary to congenital heart disease

In patients with repaired tetralogy of Fallot (TOF), pulmonaryregurgitation is common after surgical relief of right outflow tract ob-struction using a transannular patch and may lead to progressive rightventricular (RV) dilatation and dysfunction with age.1 Assessing RV

sion of Pediatric Cardiology, Department of Pediatrics (M.K., B.N.,

.R., A.G.), the Institute for Medical Informatics, Statistics and

n (A.A.), the Division of Pediatric Radiology, Department of

.S.), and the Institute of Physiological Chemistry, Centre of

Medicine (G.C.), Medical University Graz, Graz, Austria; the

diatric Cardiology, Johns Hopkins University School of Medicine,

ryland (W.R.).

sts: Martin Koestenberger, PhD, MD, Medical University Graz, De-

ediatrics, Auenbruggerplatz 34/2, A-8036 Graz, Austria (E-mail:

nberger@medunigraz.at).

6.00

2 by the American Society of Echocardiography.

rg/10.1016/j.echo.2012.06.004

volume and systolic function in these patients is of interest.Recently, quantification of RV size and function by echocardiographyhas been compared with angiography2 andmagnetic resonance imag-ing (MRI).3 RV volumes determined by three-dimensional echocardi-ography were found to be comparable to MRI data.4 New indices forthe assessment of RV function have been published, including tricus-pid annular plane systolic excursion (TAPSE)5 and tricuspid annularpeak systolic velocity (S0).6 S0, measured using Doppler tissue imaging(DTI), has been suggested as a good quantitative parameter of RVsystolic function.6,7 Studies of pulsed-wave DTI measurements of S0

have been reported in children.8-10 Reference values and calculatedZ-score values of S0 in healthy pediatric patients have beendetermined recently.11 A few newer studies have shown that S0

may be a reproducible index of systolic RV function in patientswith congenital heart disease (CHD).12,13 Still, little is known aboutS0 values in pediatric and young adult patients with repaired TOFor with pulmonary artery hypertension (PAH) secondary to CHD(PAH-CHD).

1

Abbreviations

BSA = Body surface area

CHD = Congenital heart

disease

CI = Confidence interval

DTI = Doppler tissue imaging

MRI = Magnetic resonance

imaging

PAH = Pulmonary artery

hypertension

PAH-CHD = Pulmonary

artery hypertension secondaryto congenital heart disease

RV = Right ventricular

RVEDVi = Right ventricularend-diastolic volume index

RVEF = Right ventricularejection fraction

TAPSE = Tricuspid annular

plane systolic excursion

TOF = Tetralogy of Fallot

TR = Tricuspid regurgitation

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

The primary aim of this studywas to determine S0 values in pe-diatric patients and young adultswith RV volume overload (TOF)and severe pressure overload(PAH-CHD) and to comparewith normal values in a cross-sectional study design. A second-ary aim was to compare these S0

values with the RV ejectionfraction (RVEF) and RV end-diastolic volume index (RVEDVi)values measured by MRI. The fi-nal aim was to compare RVEFand RVEDVi values with age inchildren and young adults withPAH-CHD and TOF.

METHODS

Patient Population

All patient data were collected ina prospective manner at ourinstitutions.

Group 1 consisted of 55 pa-tients with PAH-CHD (agerange, 0.6–34 years; mean age,13.2 years; 34 male, 21 female;body surface area [BSA] range,

0.35–2.08 m2). Thirty-one patients with PAH-CHD were aged# 18 years, and 24 were aged > 18 years. Patients with PAH wereall associated with CHD according to the 2009 updated clinical clas-sification of pulmonary hypertension (group 1.4.4).14 The cardiac di-agnoses and the baseline characteristics of the patients are shown inTable 1. Patients with more than moderate atrioventricular valve re-gurgitation or conduit regurgitation were excluded from this study.The respective CHDs were repaired in all patients at a mean age of5.4 months (range, 0.5–15.8 months). None of our patients hadEisenmenger syndrome, the most advanced form of PAH-CHD. Atthe time of enrollment, all patients were in clinically stable condition,with no new medications started within the previous 3 months.Echocardiographic studies were performed in a cross-sectional man-ner over a wide range of intervals between operation and the timeof echocardiography. All these patients had measurable mild to mod-erate tricuspid regurgitation (TR) jets; patients with severe TR wereexcluded from the study. RV systolic pressure was assessed by TR ve-locity (calculated from the modified Bernoulli equation).15 TR veloc-ity > 2.8 m/sec (corresponding to a right atrioventricular pressuregradient > 31 mm Hg) is considered a reasonable cutoff to define el-evated pulmonary pressures in the absence of pulmonary stenosis.16

TR was measured in all of our patients at least as half of systemic sys-tolic pressure, apart from three patients in whommild TR made it im-possible to obtain reliable data. Twenty-seven of our patients withPAH-CHD (49% of all patients) underwent MRI. The time intervalbetween the MRI and echocardiography had a mean of 37 days(range 0 to 117 days). All patients underwent right-heart catheteriza-tion, which remains the gold standard for diagnosing PAH. Left-sidedfilling pressure and cardiac output data were obtained to rule out en-tities that can elevate pulmonary artery pressure other than pulmo-nary vascular disorders, such as pulmonary venous hypertension.

PAH was defined as a mean pulmonary artery pressure $ 25 mmHg at rest, a pulmonary capillary wedge pressure < 15 mm Hg, andpulmonary vascular resistance $ 3 mm (Wood units � BSA[m2]).17 By directly measuring pressures and indirectly measuringflow, we determinedmarkers such as cardiac output (using Fick’s prin-ciple), mixed venous oxygen saturation, and mean pulmonary arterypressure. Right-heart catheterization data were as follows: mean pul-monary artery pressure ranged from 30 to 65 mm Hg (mean, 39.2mm Hg) at rest, pulmonary vascular resistance ranged from 3.8 to20.2 Wood units � BSA (m2) (mean, 5.6 Wood units � BSA [m2]),and mean mixed venous oxygen saturation was 65 6 9% in allpatients with PAH-CHD (Table 1). The time interval between right-heart catheterization and echocardiography ranged from 0 to 52days. All patients had RV systolic pressure$62% of systemic systolicpressure. Twelve patients with initial diagnostic catheterization at thetime of this study underwent first-time vasodilator testing.

Group 2 consisted of 183 patients with repaired TOF (79male, 104female) who were undergoing routine clinical follow-up. The RVoutflow tract was repaired by means of a transannular patch madeof autologous untreated pericardium in all patients at a mean age of8.7 months (range, 3.3–18.9 months). The patients were evaluatedfrom the newborn age to the age of 34 years (mean age, 15.2 years).Echocardiographic studies were performed in a cross-sectional man-ner over a wide range of intervals between operation and the timeof echocardiography. One hundred five patients with TOF wereaged # 18 years, while 78 patients were aged > 18 years. Patientsin group 2 had a mild mean residual RV outflow tract gradient of16 6 8 mm Hg, as determined by routine echocardiography. Thebaseline characteristics of the patients and their medications areshown in Table 2. Patients with repaired TOF with higher degreesof RVoutflow tract obstruction or valvular or pulmonary artery branchstenosis were excluded from the study. In 33 patients (18% of all pa-tients with TOF), RVoutflow tract aneurysms were present. Thirteenpatients with restrictive physiology of the right ventricle, defined as thepresence of laminar antegrade diastolic main pulmonary artery flowthroughout the respiratory cycle by Doppler echocardiography,18

were excluded from the study. We used previous MRI data of 41 pe-diatric patients with TOF19,20 (i.e., 37% of 111 study patients hadMRIscans available for the current study), while all echocardiographic datawere acquired solely for this study. Thirty-nine patients (21% of allpatients with TOF) underwent aortopulmonary shunt proceduresbefore surgical repair. In 111 patients (61% of all patients with TOF),S0 could be compared with RVEF and RVEDVi measured by MRI.The time interval between MRI and echocardiography ranged from0 to 43 days. Recordings and measurements of S0, RVEDVi, andRVEF were performed without and with access to MRI data.

Group 3 consisted of 849 healthy patients (428 male, 421 female)with normal results on echocardiography and measured S0 values in-side the previously published age-related normal Z-score range.11

Patients were selected from individuals referred to our cardiology ser-vice for evaluation of heart murmurs or family history of heart disease.The study group encompassed neonates to adolescents (age range, 1day to 18 years; BSA range, 0.18–2.30 m2) and was compared withour patients with PAH-CHD and TOF. For the purposes of the study,only echocardiograms with official readings of completely normal re-sults or completely normal results except for patent foramen ovalewith diameter # 2 mm were accepted for analysis. All patients withCHD, acquired heart disease, or chromosomal syndromes wereexcluded from analysis. Patients were examined in a resting statewithout prior sedation. Infants were allowed to be bottle fed duringthe examination.

Table 1 Demographic data of patients with PAH-CHD

Variable Value

All (outpatients) 94Patients fulfilling inclusion criteria 55

Female 21Age (y), mean (range) 13.2 (0.6–34)

BSA (m2), range 0.35–2.08

New York Heart Association

functional class

I 11

II 26

III 12

Time of surgical repair (mo),

mean (range)

5.4 (0.5–15.8)

DiagnosisAtrioventricular septal defect 23

VSD 16

Pulmonary atresia with VSD 11

Total anomalous pulmonary

venous return

5

Treatment

Bosentan 11Bosentan plus sildenafil 15

Sildenafil 17Calcium antagonists 6

Furosemide 21

Warfarin 12

EchocardiographyS0 data available 55

Mild TR 16Moderate TR 39

MRIPatients with PAH 27

RVEDVi (mL/m2), mean 6 (range) 147.3 6 40.2 (87–238)RVEDVi > 150 mL/m2 (% of measured) 13 (48%)

RVEF (%)>50 3

40–50 9

30–40 11

<30 4Electrocardiography

Patients with PAH 49QRS duration (msec), mean 6 (range) 126 6 33 (80–220)

QRS duration $ 180 msec(% of measured)

4 (8.2%)

Right-heart catheterization

Mean pulmonary artery pressure

(mm Hg), mean (range)

39.2 (30–65)

Pulmonary vascular resistance(Wood units), mean (range)

5.6 (3.8–20.2)

Mixed venous saturation (%),mean 6 SD

65 6 9

VSD, Ventricular septal defect.

Table 2 Demographic data of patients with TOF

Variable Value

All (outpatients) 296Patients fulfilling inclusion criteria 183

Female 104Age (y), mean (range) 15.2 (0–34)

BSA (m2), range 0.18–2.30

New York Heart Association functional

class

I 131

II 52

Time of surgical repair (mo), mean

(range)

8.7 (3.3–18.9)

Aortopulmonary shunts (% ofmeasured)

39 (21%)

EchocardiographyS0 data available 183

Residual pulmonary stenosis (mm Hg),mean 6 SD

16 6 8

MRI

Patients with TOF 111

RVEDVi (ml/m2), mean 6 SD (range) 140.6 6 37.9 (69–228)

RVEDVi > 150 mL/m2 (% of measured) 43 (38.1%)

Regurgitation fraction (%), mean 6 SD

(range)

38.8 6 15.5 (18–71)

ElectrocardiographyQRS duration (msec), mean 6 SD

(range)

153 6 26 (70–210)

QRS duration $ 180 msec (% of

measured)

11 (7%)

Journal of the American Society of EchocardiographyVolume - Number -

Koestenberger et al 3

Echocardiographic Techniques

Echocardiography was performed using the Sonos iE33 echocardio-graphic system (Philips Medical Systems, Andover, MA) with trans-ducers of 5-1, 8-3, and 12-4 MHz depending on patient size.Images were recorded digitally and later analyzed by one of the

investigators (M.K.) using offline software (Xcelera Echo; PhilipsMedical Systems, Eindhoven, The Netherlands).

Pulsed-wave DTI was performed using transducer frequencies of2.5 to 3.5 MHz with spectral Doppler filters adjusted until a Nyquistlimit of 15 to 20 cm/sec was reached. The minimal optimal gain set-ting was used. Doppler measurements were acquired with subjectsin the lateral decubitus position during shallow respiration. Guidedby the four-chamber view, a 5-mm sample volume was placed atthe lateral corner of tricuspid annulus, exactly at the attachmentof the anterior leaflet of the tricuspid valve. Care was taken to ob-tain an ultrasound beam parallel to the direction of tricuspid annularmotion. Peak annular velocities during systole were recorded andanalyzed offline. The resulting velocities were recorded for threeto five cardiac cycles and were averaged. To assess day-to-dayvariability of S0, pulsed-wave DTI was repeated 24 hours later underthe same conditions in 22 subjects. The investigation of S0 wasperformed in a quiet state. RV conditions were assessed. Patientswere classified as having RV pressure overload on the basis ofelevated TR velocities, RV outflow tract gradients, and/or systolicseptal flattening.

MRI

RV volumes were quantified by means of breath-hold cine steady-state free precession sequences in 111 patients with repaired TOFand 27 patients with PAH-CHD using a 1.5-T machine (Symphony;

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

Siemens Medical Systems, Forchheim, Germany). Patients withimplantable cardioverter-defibrillators were excluded from this studybecause MRI is contradicted in patients with such implants. The rightventricle was encompassed by means of continuous short-axis viewsfrom base to apex. RV volumes were calculated after delineation ofthe endocardial surfaces of the end-diastolic and end-systolic images.Multiplication of the delineated cavity area by the slice thicknessyielded the slice volume, and summation of all slice volumes yieldedventricular volume at end-diastole and end-systole. Values of RVEDVi> 150 mL/m2 were defined on the basis of MRI data reported foradults and adapted for the pediatric age group, corresponding to150% of the upper limit of normal for RVEDVi in children, which is100 mL/m2.21 Pulmonary regurgitation was quantified by velocity-encoded imaging. The regurgitation fraction was determined bycalculating the percentage of reverse volume from forward volume.All volume and flow measurements were indexed for BSA and ex-pressed as milliliters per beat per square meter. Measurements weremade by E.S. blinded to the echocardiographic data.

Statistical Analysis

All S0 data were measured by three well-trained observers (M.K, B.H.,and B.N.) from three to five consecutive beats and averaged. For dataanalysis, SPSS version 19 (SPSS, Inc., Chicago, IL) and SAS version9.2 (SAS Institute Inc., Cary, NC) were used. Data are presentedas mean 6 2 SDs. In a first-step analysis in the healthy controls,the correlation between age and S0 was analyzed using Pearson’scorrelation coefficient. A regression was used to estimate in healthypatients S0 from age. In a second step in patients with PAH-CHD andTOF, the deviation from normal S0 values was calculated. A regres-sion was used to estimate in patients with PAH-CHD and repairedTOF the deviation of normal S0 from age. The cutoff value for thisage, at which the S0 value in patients with PAH-CHD and repairedTOF is lower than the reference value, was taken from this linearregression analysis. This was done by using the lower bound of the62-SD interval of the mean value of normal S0. The correlationstructure between age and MRI-determined RVEF and RVEDVi inthe TOF and PAH-CHD groups was analyzed using Pearson’s corre-lation coefficient.

Interobserver variability was also assessed. Data were measured bytwo observers (M.K. and B.N.) who were blinded to each other’sresults. Intraobserver variability was considered in 24 participantsby repeating the measurements on two occasions. Interobserverand intraobserver variability was found for S0, with intraclass correla-tion coefficients of 0.97 (confidence interval [CI], 0.94–0.99; P <.001) and 0.98 (CI, 0.96–0.99; P < .0001). Intraobserver and interob-server variability in our study was similar to that reported in theliterature for S0.6,22

Ethics

This study was in compliance with all institutional guidelines relatedto patient confidentiality and research ethics, including institutionalreview board approval (EK-Nr. 23-059 ex 11/12).

RESULTS

Data from Healthy Subjects

S0 and age were correlated in our control group: Pearson’s correlationcoefficient was 0.64 for age and S0 (P < .001) and 0.67 for BSA and S0

(P< .001). There was no statistically significant difference of normal S0

values between female and male patients (P = .95). Normal S0 valuesincrease with age, as shown previously.11 Regression analysis revealedthat 56.9% of the variance in S0 could be explained using a regressionmodel by age alone. These results show that adding BSA resulted inonly a minor increase of explained variance (57.1%). The regressionequation relating age and predicted S0 in healthy patients was pre-dicted S0 = 7.599 + 3.157 � age1/2 � 0.414 � age. For calculatingCIs, the residual SD of 1.7 was used.

S0 Values in Patients with PAH-CHD and Repaired TOF

A representative image of S0 in an 18-year-old patient with PAH-CHD and a 16-year-old adolescent is shown in Figure 1. For patientsup to 18 years of age, S0 was analyzed by calculating the deviation tonormal to the age S0 values as estimated above (S0D). For patientsaged > 18 years, the deviation to the maximum predicted S0 valueof patients aged 18 years (13.5 cm/sec) was used. S0D values inpatients with PAH-CHD and in those with repaired TOF showedsignificantly different courses compared with normal controls. Inpatients with PAH-CHD, a negative correlation (r = �0.76, P <.001) was found between increasing age and S0D values (Figure 2).In patients with repaired TOF, a negative correlation (r = �0.69,P < .001) was found between age and S0D values (Figure 2). By re-gression analysis, 71.2% of the variance in S0D in patients withPAH-CHD and 62.7% of the variance in S0D in patients with TOFcould be explained. Considering values outside of the 62-SDinterval of S0 in healthy subjects, the age at which patients withPAH-CHD and repaired TOF leave this interval was calculated.Therefore, the regression equation of S0D for patients withPAH-CHD and repaired TOF was used. S0 values in patients withPAH-CHD were significantly reduced after 10.4 years of age, andS0 values in patients with repaired TOF were significantly reducedafter 13.6 years of age compared with the lower bound of the�2-SD interval of normal controls (Figure 2).

MRI Data of Patients with PAH-CHD and Repaired TOF

For patients with PAH-CHD, the data were as follows: RV volumeoverload was seen by a mean RVEDVi of 147.3 6 40.9 mL/m2

(range, 87–238 mL/m2) in all of our 27 patients with PAH-CHD(mean age, 14.8 years) measured by MRI (Table 1). The correlationcoefficient between RVEDVi and S0 was r = �0.59 (CI, �0.79 to�0.27; P < .001) and between RVEDVi and S0D was r = �0.64(CI,�0.82 to�0.35; P< .001) (Figure 3). RVEFs were >50% in threepatients, between 40% and 50% in nine patients, between 30% and40% in 11 patients, and #30% in four patients with PAH-CHD. Apositive correlation between RVEF and S0 (r = 0.82; CI, 0.64 to0.91; P < .001) and a positive correlation between RVEF and S0D(r = 0.88; CI, 0.75 to 0.95; P < .001) was seen in all patients withPAH-CHD (Figure 4). A positive correlation was observed betweenage and RVEDVi (r = 0.71; CI, 0.46 to 0.86; P < .001) in all patientswith PAH-CHD (Figure 5), and a negative correlation (r =�0.71; CI,�0.85 to �0.45; P < .001) was seen between age and RVEF(Figure 6).

For patients with repaired TOF, the data were as follows: With in-creasing postoperative period, significant RV volume overload wasseen (mean RVEDVi, 140.66 37.9 mL/m2; range, 69–228 mL/m2),as measured in all of our 111 patients with TOF (mean age, 16.1 years)who underwent MRI (Table 2). The correlation between RVEDVi andS0D was r = �0.35 (CI, �0.50 to �0.18; P < .001) and betweenRVEDVi and S0 was r = �0.29 (CI, �0.45 to �0.11; P = .002) in

Figure 1 Apical four-chamber view. The white broken line indicates M-mode cursor placement at the tricuspid lateral annulus. Rep-resentative image of DTI-measured S0 in an 18-year-old patient with PAH-CHD (A) and in a 16-year-old healthy adolescent (B).

Journal of the American Society of EchocardiographyVolume - Number -

Koestenberger et al 5

repaired patients with TOF (Figure 3). Positive correlations were seenbetween RVEF and S0 (r = 0.66; CI, 0.54 to 0.75; P < .001) andbetween RVEF and S0D (r = 0.70; CI, 0.58 to 0.78; P < .001) in allpatients with TOF (n = 111) investigated by MRI (Figure 4). A positivecorrelation was observed between age and RVEDVi (r = 0.29; CI,0.11 to 0.45; P < .002; Figure 5), and a negative correlation (r =–0.47; CI, �0.60 to �0.31; P < .001) was seen between age andRVEF (Figure 6).

DISCUSSION

The systolic velocity of the tricuspid annulus of the RV free wall hasbeen shown to be a reliable indicator of global RV systolic function.5,6

The tricuspid annulus has been shown to have the greatest motionalong its lateral aspect in healthy adults.23 Harada et al.13 showed

that for patients with TOF after surgical repair, the mean velocityduring systolic ejection was lower compared with control subjects.In a group of 22 patients who underwent surgical repair of TOF,decreased RV myocardial velocity compared with control subjectswas demonstrated.24 Meluzin et al.6 demonstrated that S0 < 11.5cm/sec can predict RV impairment in adults. A similar cutoff value(S0 < 10.8 cm/sec) was found in adults to be a predictor of poor prog-nosis in patients with dilated cardiomyopathy.25,26 Recentlypublished guidelines for the assessment of right-heart function inthe adult population confirmed that S0, measured by DTI, is a simpleand reproducible measure to assess basal free wall function, and theyrecommend that S0 < 10 cm/sec should raise suspicion for abnormalRV function.27

Normal S0 values have recently been published for healthy chil-dren,11 and S0 has been reported to be abnormal in patients withCHD.28We found that S0 values correlate with TAPSEmeasurements

Figure 2 Deviation of S0 values (S0D) in patients with PAH-CHD

and thosewith repaired TOF frommean reference values plottedagainst increasing age. The S0

D value data points for patientswith PAH-CHD and repaired TOF are represented by blue dia-monds and red triangles, respectively. The interpolated meanvalues of the control group are represented by the black line.The �2-SD line of the control group measurements is repre-sented by the black smooth-dashed line. The absolute deviationof the measured mean S0 values of our patients compared withage-related S0 reference values (interpolated black thin line) isdemonstrated. The red line is an interpolation for a linear trendfor patients with repaired TOF and the blue broken line for thosewith PAH-CHD.

Figure 3 Relationship between S0 values andRVEDVi in patientswith PAH-CHD and repaired TOF. S0

D value data are repre-sented by blue diamonds for patients with PAH-CHD and redtriangles for patients with repaired TOF. Deviation of S0

D valuesin patients with PAH-CHD and repaired TOF from mean age-related reference values is shown. The horizontal broken lineat zero indicates normal S0 values. The blue broken and solidred lines are interpolations for linear trends in patients withPAH-CHD and repaired TOF, respectively.

Figure 4 Relationship between S0 values and RVEF in patientswith PAH-CHD and repaired TOF. S0

D values are representedby blue diamonds for patients with PAH-CHD and red trianglesfor those with repaired TOF. Deviation of S0

D values in patientswith PAH-CHD and TOF from mean age-related referencevalues is shown. The horizontal broken line at zero indicatesnormal S0 values. The blue broken and the solid red lines areinterpolations for linear trends in patients with PAH-CHD andthose with repaired TOF, respectively.

6 Koestenberger et al Journal of the American Society of Echocardiography- 2012

in healthy pediatric subjects.11 Similar to our data, a significant corre-lation between S0 and TAPSE has been shown in adults with PAH.7

Because this group compared its data with adult values, this conse-quently cannot be extrapolated to children. The correlation of S0

and TAPSE in our children was shown to be significant but weak(r = 0.260).11 An explanation might be the different age-related in-crease of TAPSE and S0 values during childhood. In our opinion, con-sequently, one measurement cannot replace the other for theappropriate determination of systolic RV function in a pediatric pop-ulation. So far, S0 has not been prospectively investigated for RV func-tion assessment in a sizable pediatric population with repaired TOFand/or PAH-CHD.

Abd el Rahman et al.29 showed persistent postoperative RV systolicand diastolic dysfunction in postoperative patients with TOF. In ourpatients with repaired TOF, who underwent surgical repair in earlylife, S0 was found to be significantly reduced comparedwith publishednormal values11 when measured in a cross-sectional manner inpatients aged $ 13.6 years. This indicates that RV systolic functionis significantly reduced after this time interval, most likely becauseof long-standing pulmonary regurgitation and RV volume overload.This is supported by a significant positive correlation between S0

and RVEF and by a significant negative correlation of S0 andRVEDVi in our study.

Bogaard et al.30 showed that in patients with PAH-CHD, an impor-tant adaptation of the right ventricle to high pressure is to increasewall thickness by accumulating muscle mass (hypertrophy) and toassume a more rounded shape. Among adults with PAH, only about

11% have PAH-CHD,31 which is in contrast to children, in whomabout half of those with PAH have underlying CHD.32 Althoughmany cases of PAH-CHD begin in childhood, the demographicshave changed with an increased prevalence of CHD in recent

Figure 5 Relationship between age and RVEDVi in patients withPAH-CHD and repaired TOF. S0

D values are represented by bluediamonds for patients with PAH-CHD and red triangles for thosewith repaired TOF. The blue broken and solid red lines are inter-polations for linear trends in patients with PAH-CHD and thosewith repaired TOF, respectively.

Figure 6 Relationship between age and RVEF in patients withPAH-CHD and repaired TOF. S0

D values are represented byblue diamonds for patients with PAH-CHD and red trianglesfor those with repaired TOF. The blue broken and the solid redlines are interpolations for linear trends in patients withPAH-CHD and those with repaired TOF patients.

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Koestenberger et al 7

years, possibly because of more pediatric patients’ surviving intoadulthood.33 With progress in cardiac surgery, there is an increasein the number of patients with complex physiology whomay developpulmonary vascular lesions after surgical repairs in early childhood, asin our patients.34 In a recent study Fang et al.35 demonstrated that RVlong-axis function is sensitive in revealing RV myocardial damage inpatients with chronic pressure overload. PAH-CHD has been shownto be essentially the same in adults and in the pediatric age group, al-though there may be differences reflecting the natural history ofPAH.36 PAH-CHD has been described to be an ongoing, progressivedisease, as some patients may present with less (albeit increasingly)severe PAH-CHD at an advanced age.36

Little is known of systolic RV function in PAH-CHD in the pediat-ric age group. Because of the preserved RV systolic function in our in-fants and young children with PAH-CHD, we assume that they werein the stage of ‘‘adaptive hypertrophy,’’ as described by Bogaard et al.30

S0 values in patients with PAH-CHD become significantly reducedcompared to controls after the age of 10.4 years (i.e., the longer theright ventricle experiences severe pressure overload, the more de-pressed systolic RV function becomes). This might be explained bythe fact that the right ventricle cannot sustain high long-term pressureoverload over a long period of time.30

Advances in the field of cardiac MRI established this technique asthe ‘‘gold standard’’ for the assessment of RV volume and RV functionin children and in adults.21 In our subjects with PAH-CHD, a signifi-cant positive correlation was found between S0 and RVEF, anda significant negative correlation was found between S0 andRVEDVi, supporting the value of the measured S0 data. Our mea-sured S0 values confirm the decreased RVEF and increased RVEDVimeasurements using the MRI in adolescents and young adults withPAH-CHD. Therefore, we assume that long-standing severe RV pres-sure overload also leads to ‘‘maladaptive cardiac growth and contrac-tile function,’’ as generally has been described for PAH,30 also in ourpatients with PAH-CHD. The increased RVEDVi can be explained bythe fact that with increasing afterload, the ventricular septum be-

comes flat and eventually inverts into the left ventricular cavity withtime. Geometry and rate of contraction of the right ventricle changeand therefore might explain the reduced RVEF and S0 in patients withPAH-CHD.

Limitations

A limitation of our study is that invasive data were available only inpatients with PAH-CHD but not in those with repaired TOF, particu-larly on absolute pulmonary artery pressure, which might have ex-plained other contributing factors. We did not assess the effects ofpreload variations related to respiration. In pediatric clinical practice,it would be cumbersome to apply respiratory gating to this method ona routine basis. Although S0 is a good parameter to assess RV function,it does not take into account segmental RV function. The populationdescribed in the present study was relatively small, because patientswere enrolled at only two centers. It cannot be excluded that recentadvances in surgery may have affected our results. S0 is not a goodparameter to assess preload and afterload variations for the rightventricle but simply reflects impaired RV function of our patientswith repaired TOF and of our patients with PAH-CHD. We cannotexclude the possibility that the patient population enrolled in thisstudy was biased toward more significant residual lesions after trans-annular patch repair for our patients with TOF. We excluded patientswith TOF with additional lesions, and by doing so, our study popula-tion may not be representative of a larger population of patients withrepaired TOF. A sedation protocol for right-heart catheterization andechocardiography does exist at our institution, but the adapting ofdrug doses and the use of additional drugs if necessary were left tothe discretion of the treating cardiologist.

CONCLUSIONS

Our results show that in infants and young children with repairedTOF and PAH-CHD, S0 values were similar to those in our healthy

8 Koestenberger et al Journal of the American Society of Echocardiography- 2012

patients. We demonstrate that persistent volume overload in patientswith repaired TOF led to an increase in RVEDVi and a decrease in RVsystolic function, measured by RVEF and S0 onMRI. Interestingly, ourpatients with PAH-CHD showed similar changes. Persistent ongoingpressure overload seems to reduce RVEF and S0 and increaseRVEDVi with time in this patient group. This occurred at a youngerage than in the repaired TOF group, suggesting that the regurgitantvolume can better tolerate chronic volume overload comparedwith chronic pressure overload.

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