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Diastolic and systolic right ventricular diameters for predicting pulmonary hypertension in children with congenital heart disease

Open AccessPublished:October 21, 2020DOI:https://doi.org/10.1016/j.clinimag.2020.10.027

      Highlights

      • In children with PH, an association is found between ECG-CTA-gated image parameters and PH.
      • Diastolic-RVD & systolic-RVD are associated with pulmonary arterial systolic pressure.
      • Patients with D-RVD-BSA over 6.86 had significantly higher risk of PH.
      • Patients with S-RVD-BSA over 5.87 had significantly higher risk of PH.
      • The AUCs of diastolic-RVD and systolic-RVD were 0.907 and 0.917, respectively.

      Abstract

      Prospective electrocardiography (ECG)-gated cardiac computed tomography angiography (CTA) is widely used for pediatric patients with congenital heart disease (CHD) due to the lower radiation dose compared with the ECG-gated technique. However, functional parameters acquired using ECG-gated cardiac CT to predict pulmonary hypertension (PH) in children with CHD have not yet been reported. This study aimed to investigate the potential of diastolic and systolic right ventricular diameters (RVD) on prospective ECG-gated cardiac CTA to predict PH in children with CHD. A total of 44 children with CHD were divided into two groups: CHD with PH (n = 22) and CHD without PH (n = 22). The association between ECG-gated CTA parameters and PH was evaluated by logistic regression. The receiver operating characteristic curve (ROC) was used to find the best cut-off point for the parameters measured by Youden's index. Patients with higher RVD-BSA [aOR (95% CI) diastolic: 2.76 (1.23–6.23); systolic: 6.15 (1.72–22.06)] had higher risk of PH after adjusting for age and patent ductus arteriosus. The area under the curve (AUC) of D-RVD-BSA was 0.907 and the AUC of S-RVD-BSA was 0.917. Logistic regression showed that patients with D-RVD-BSA over 6.86 or S-RVD-BSA over 5.87 had significantly higher risk of PH after adjustments (aOR = 23.52, 95% CI = 2.89–191.03; aOR = 31.14, 95% CI = 2.75–352.85). In conclusion, in children with CHD, measurements of diastolic or systolic BSA-modified RVDs on prospective ECG-gated CTA are non-invasive markers of PH. BSA-modified D-RVD of 6.86 or BSA-modified S-RVD of 5.87 may be used to identify PH in children with CHD.

      Keywords

      1. Introduction

      Echocardiography is traditionally the first-line imaging modality used for patients with congenital heart disease (CHD). Pulmonary hypertension (PH) in adult is defined as an increase in mean pulmonary arterial pressure (PAP) > 20 mm Hg to 25 mm Hg at rest in accordance with guidelines of the American Heart Association (AHA) and American Thoracic Society [
      • Abman S.H.
      • Hansmann G.
      • Archer S.L.
      • Ivy D.D.
      • Adatia I.
      • Chung W.K.
      • et al.
      Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society.
      ] and the European Society of Cardiology [
      • Galiè N.
      • Humbert M.
      • Vachiery J.L.
      • Gibbs S.
      • Lang I.
      • Torbicki A.
      • et al.
      2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
      ]. Right ventricular (RV) function determines both the degree of symptoms and survival among patients with PH, and RV failure remains the common fatal pathway and consequence of PH [
      • Lim S.
      • Lee H.
      • Lee S.J.
      • Kim J.K.
      • Suh J.
      • Lee E.H.
      • et al.
      CT signs of right ventricular dysfunction correlated with echocardiography-derived pulmonary arterial systolic pressure: incremental value of the pulmonary arterial diameter index.
      ]. Previous studies with adult patients have used a PASP > 40 mm Hg assessed via right heart catheterization as a cut-off value for defining PH [
      • Lim S.
      • Lee H.
      • Lee S.J.
      • Kim J.K.
      • Suh J.
      • Lee E.H.
      • et al.
      CT signs of right ventricular dysfunction correlated with echocardiography-derived pulmonary arterial systolic pressure: incremental value of the pulmonary arterial diameter index.
      ,
      • Gupta H.
      • Ghimire G.
      • Naeije R.
      The value of tools to assess pulmonary arterial hypertension.
      ,
      • Kanbayashi K.
      • Minami Y.
      • Haruki S.
      • Maeda R.
      • Itani R.
      • Ashihara K.
      • et al.
      Association of elevated pulmonary artery systolic pressure with stroke and systemic embolic events in patients with hypertrophic cardiomyopathy.
      ,
      • Lee H.
      • Kim S.Y.
      • Lee S.J.
      • Kim J.K.
      • Reddy R.P.
      • Schoepf U.J.
      Potential of right to left ventricular volume ratio measured on chest CT for the prediction of pulmonary hypertension: correlation with pulmonary arterial systolic pressure estimated by echocardiography.
      ]. Although defining PH is currently based on invasive cardiac catheterization, transthoracic echocardiogram is the initial diagnostic tool used to confirm suspicions of elevated pulmonary pressure when PASP is above 40 mm Hg [
      • Lim S.
      • Lee H.
      • Lee S.J.
      • Kim J.K.
      • Suh J.
      • Lee E.H.
      • et al.
      CT signs of right ventricular dysfunction correlated with echocardiography-derived pulmonary arterial systolic pressure: incremental value of the pulmonary arterial diameter index.
      ,
      • Kanbayashi K.
      • Minami Y.
      • Haruki S.
      • Maeda R.
      • Itani R.
      • Ashihara K.
      • et al.
      Association of elevated pulmonary artery systolic pressure with stroke and systemic embolic events in patients with hypertrophic cardiomyopathy.
      ]. Noninvasive Doppler echocardiography offers several variables that correlate closely with right heart hemodynamics, including PASP, therefore echocardiography PASP was applied as screening cutoff for defining suspected PH in this study.
      Multidetector CT (MDCT) has been used increasingly for imaging patients with CHD, because it provides high-quality three-dimensional images enabling evaluation of complex heart structures. In pediatric patients, the indications for CT are CHD with complex and heterogeneous nature needing detailed assessment (e.g., associated with abnormal coronary arteries, including transposition of the great arteries [TGA], tetralogy of Fallot [TOF], truncus arteriosus and double-inlet left ventricle), and also for critical cases with unstable hemodynamic status, requiring examination with less life-threatening risk [
      • Gupta H.
      • Ghimire G.
      • Naeije R.
      The value of tools to assess pulmonary arterial hypertension.
      ,
      • Lee H.
      • Kim S.Y.
      • Lee S.J.
      • Kim J.K.
      • Reddy R.P.
      • Schoepf U.J.
      Potential of right to left ventricular volume ratio measured on chest CT for the prediction of pulmonary hypertension: correlation with pulmonary arterial systolic pressure estimated by echocardiography.
      ]. However, few CT-based parameters are currently available for use in predicting PH in patients with CHD. Previous studies have reported that several parameters obtained with cardiac magnetic resonance imaging and CT, including the ratio of the main pulmonary artery (MPA) and the ascending aorta diameters (AA), the right ventricular maximal diameter, the ratio of right and left ventricular diameters, the ratio of right and left ventricular volumes, and the septal eccentricity index (SEI), can be used to predict PH in adults [
      • Spruijt O.A.
      • Bogaard H.J.
      • Heijmans M.W.
      • Lely R.J.
      • van de Veerdonk M.C.
      • de Man F.S.
      • et al.
      Predicting pulmonary hypertension with standard computed tomography pulmonary angiography.
      ,
      • Lewis G.
      • Hoey E.T.
      • Reynolds J.H.
      • Ganeshan A.
      • Ment J.
      Multi-detector CT assessment in pulmonary hypertension: techniques, systematic approach to interpretation and key findings.
      ,
      • Aviram G.
      • Shmueli H.
      • Adam S.Z.
      • Bendet A.
      • Ziv-Baran T.
      • Steinvil A.
      • et al.
      Pulmonary hypertension: a nomogram based on CT pulmonary angiographic data for prediction in patients without pulmonary embolism.
      ,
      • Shen Y.
      • Wan C.
      • Tian P.
      • Wu Y.
      • Li X.
      • Yang T.
      • et al.
      CT-base pulmonary artery measurement in the detection of pulmonary hypertension: a meta-analysis and systematic review.
      ,
      • Corson N.
      • Armato 3rd, S.G.
      • Labby Z.E.
      • Straus C.
      • Starkey A.
      • Gomberg-Maitland M.
      CT-based pulmonary artery measurements for the assessment of pulmonary hypertension.
      ,
      • Sauvage N.
      • Reymond E.
      • Jankowski A.
      • Prieur M.
      • Pison C.
      • Bouvaist H.
      • et al.
      ECG-gated computed tomography to assess pulmonary capillary wedge pressure in pulmonary hypertension.
      ]. To date, only few studies have presented useful parameters for predicting PH in children. For example, a CT-measured MPA/AA of 1.3 was identified to be indicative of PAH in children by using non-gating 64-slice MDCT [
      • Critser P.J.
      • Higano N.S.
      • Tkach J.A.
      • Olson E.S.
      • Spielberg D.R.
      • Kingma P.S.
      • et al.
      Cardiac magnetic resonance imaging evaluation of neonatal bronchopulmonary dysplasia-associated pulmonary hypertension.
      ,
      • Caro-Dominguez P.
      • Compton G.
      • Humpl T.
      • Manson D.E.
      Pulmonary arterial hypertension in children: diagnosis using ratio of main pulmonary artery to ascending aorta diameter as determined by multi-detector computed tomography.
      ].
      Prospective electrocardiography (ECG)-gated cardiac computed tomography angiography (CTA) (step-and-shoot mode) is widely used for pediatric patients with CHD due to the lower radiation dose compared with the ECG-gated technique [
      • Liu Y.
      • Li J.
      • Zhao H.
      • Jia Y.
      • Ren J.
      • Xu J.
      • et al.
      Image quality and radiation dose of dual-source CT cardiac angiography using prospective ECG-triggering technique in pediatric patients with congenital heart disease.
      ,
      • Young C.
      • Taylor A.M.
      • Owens C.M.
      Paediatric cardiac computed tomography: a review of imaging techniques and radiation dose consideration.
      ,
      • Jin K.N.
      • Park E.A.
      • Shin C.I.
      • Lee W.
      • Chung J.W.
      • Park J.H.
      Retrospective versus prospective ECG-gated dual-source CT in pediatric patients with congenital heart diseases: comparison of image quality and radiation dose.
      ]. These previous studies have shown that, for neonates and young children who may often require only morphological and proximal coronary artery detail, prospective ECG-triggered technique may be used to reduce the radiation dose and motion artifacts. However, functional parameters acquired using prospective ECG-gated cardiac CT to predict PH in children with CHD have not yet been reported. Therefore, this study aimed to investigate the potential of parameters from prospective ECG-gated cardiac CTA to predict PH in children with CHD.

      2. Materials and methods

      2.1 Study design and population

      The protocol for this retrospective study was approved by the institutional review board (IRB) of our hospital (B-ER-106-196), and the requirement for signed informed consent was waived due to the retrospective analysis and deidentification of patients. Prospective storage of raw prospective ECG-gated CTA data at our institution enabled retrospective reconstruction of the required image sets in this study.

      2.2 Patients

      The cohort comprised 44 children with CHD with indications for CT and who received prospective ECG-gated cardiac CTA from September 2009 to September 2015 (Fig. 1).
      Indications for CT were suspicion of heterogenous nature of congenital heart disease. The anatomy complexities in our cohort consisted of: atrial septal defect (n = 22), ventricular septal defect (n = 23), coarctation (n = 6), patent ductus arteriosus (n = 11), transposition of the great arteries (n = 1), cor triatriatum (n = 2), aortic stenosis (n = 2), large artery atherosclerosis calcified thromboembolism (n = 1), aberrant right subclavian artery (n = 3), ruptured sinus of Valsalva aneurysm (n = 1), abnormal coronary arteries distribution (n = 1), and respiratory issues (n = 13).
      The exclusion criteria were: (a) CHD with right chambers involvement; (b) an unstable disease condition or no echocardiogram available within a 3-month period; (c) structural heart disease with right ventricular outlet tract (RVOT) obstruction; pulmonary valvular stenosis, or pulmonary artery stenosis, (d) unavailability of the PASP estimated through echocardiography, (e) unavailability of raw thin-slice CT data, and (f) suboptimal image quality.
      No medication for heart rate control was used in this study group (Supplementary Table 1). All included patients were divided into PH (n = 22) or non-PH (n = 22) groups on the basis of PASP > 40 mm Hg, as described previously [
      • Gupta H.
      • Ghimire G.
      • Naeije R.
      The value of tools to assess pulmonary arterial hypertension.
      ,
      • Kanbayashi K.
      • Minami Y.
      • Haruki S.
      • Maeda R.
      • Itani R.
      • Ashihara K.
      • et al.
      Association of elevated pulmonary artery systolic pressure with stroke and systemic embolic events in patients with hypertrophic cardiomyopathy.
      ].

      2.3 Prospective ECG-gated cardiac CT protocol

      Cardiac CT was performed with a dual-source CT system (Somatom Definition Flash; Siemens Healthcare, Forchheim, Germany) using the prospective ECG-gated scan mode (step-and-shoot scan mode). The CT parameters were as follows: detector collimation, 2 × 64 × 0.6 mm; slice acquisition, 2 × 128 × 0.6 mm using a z-flying focal spot; gantry rotation time, 280 ms; quality reference mAs, 150 per rotation; and tube voltage, 80 kV. A minimum cycle time of 1.36 s for one acquisition and a subsequent table feed were required, and the temporal resolution was 75 ms.
      Prior to the scan, patients who were unable to obey commands were sedated through oral or anal administration of chloral hydrate (50–75 mg/kg) according to the patient's body weight and clinical condition. All patients were scanned in a craniocaudal direction from the shoulder to the liver dome, to ensure inclusion of the subclavian artery and entire lung parenchyma. The nonionic contrast medium iopromide (Ultravist® 30, 370 mg/ml, Bayer Schering Pharma, Berlin, Germany) was injected through a peripheral venous line using a power injection. The volume injected was adjusted according to patients' body weight: 2–3 ml/kg contrast medium (CM), followed by a normal saline flush with one third of the amount of CM, with both being administered at a flow rate of 0.3–2.0 ml/s according to the size of intravenous access. For optimum vascular opacification, a round region of interest (ROI) was defined in the descending aorta. The triggered threshold of the ROI was set at 100 HU, and the image scan began after a delay of 7–9 s. The data acquisition window center was set at 70% and 30% of the R-R interval for diastole and systole, respectively. The interval between two consecutive scans was 5 s limited by the change in scan parameters and the table movement.

      2.4 CT image analysis

      One-millimeter thin-slice CTA images were analyzed using semiautomated postprocessing three-dimensional viewer software (Aquarius iNtuition Edition Ver: 4.4.7; TeraRecon, San Mateo, CA). For this study, the selected parameters were analyzed by two independent readers, B.W. and Y.S.T., with 3 and 14 years of experience in cardiothoracic imaging, respectively, and who were unaware of the PASP or the underlying disease. All images were initially analyzed by an experienced cardiac radiologist, including disease classification. Measurements of parameters for the images were performed by a pediatric radiologist. To determine the intra-observer variability, the same pediatric radiologist analyzed the images for all patients 1 month later. All data used to analyze data from the first and second analyses were averaged to minimize intra-observer variability. In addition, an experienced cardiac radiologist, who was blinded to the initial analysis, re-evaluated the images of 50% of the patients, who were chosen at random, to determine interobserver variability.

      2.5 Modified ventricular diameter and cross-sectional area

      On two sets of images (by default, the 30% and 70% of the R-R interval), a user-selected short-axis two-chamber view was reformed to be perpendicular to the long axis of the left ventricle (LV). The plane was moved until the papillary muscle was no longer visible, and a user-selected apical four-chamber view was then reformed to visualize the maximal ventricular diameter and cross-sectional area (CSA) (Supplementary Fig. 1, Supplementary Fig. 2), according to an ideal right-ventricle-focused view defined in a guideline on right-heart evaluation [
      • Rudski L.G.
      • Lai W.W.
      • Afilalo J.
      • Hua L.
      • Handschumacher M.D.
      • Chandrasekaran K.
      • et al.
      Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography.
      ]. The modified diameter and CSA were calculated as the RVD and LVD divided by the body surface area (BSA) and the RVCSA and LVCSA divided by the BSA, respectively; measurements were obtained in both systole and diastole.

      2.6 Ventricular diameter and CSA ratios

      The RVD/LVD and RVCSA/LVCSA ratios were calculated in both systole and diastole (Supplementary Fig. 1, Supplementary Fig. 2).

      2.7 SEI

      The SEI was defined as SI/AP dimension (D2/D1) in which higher SEI reflects higher PA pressure, with reported thresholds for PH (>1.3), as described previously [
      • Averin K.
      • Michelfelder E.
      • Sticka J.
      • Cash M.
      • Hirsch R.
      Changes in ventricular geometry predict severity of right ventricular hypertension.
      ,
      • McCrary A.W.
      • Malowitz J.R.
      • Hornick C.P.
      • Hill K.D.
      • Cotten C.M.
      • Tatum G.H.
      • et al.
      Differences in eccentricity index and systolic-diastolic ratio in extremely low-birth-weight infants with bronchopulmonary dysplasia at risk of pulmonary hypertension.
      ]. SEI was calculated as the ratio of the distance between the septal–lateral wall and the anterior–posterior wall measured in the short-axis view. Diameter measurements were obtained from the short-axis two-chamber view, which was adjusted at the mitral chordal insertion level, as described previously [
      • Rudski L.G.
      • Lai W.W.
      • Afilalo J.
      • Hua L.
      • Handschumacher M.D.
      • Chandrasekaran K.
      • et al.
      Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography.
      ,
      • Ryan T.
      • Petrovic O.
      • Dillon J.C.
      • Feigenbaum H.
      • Conley M.J.
      • Armstrong W.F.
      An echocardiographic index for separation of right ventricular volume and pressure overload.
      ] (Supplementary Fig. 3).

      2.8 Interobserver agreement and intrarater reliability

      Good to excellent agreement between the results of the two observers was attained regarding functional parameters in the cardiac CT scans of 44 patients (Cohen's Kappa 0.625–0.821). In addition, the consistency of one observer's measurements of functional parameters was good (Pearson correlation coefficient: 0.772–0.980).

      2.9 Radiation dose

      To assess the radiation dose, the effective dose in millisieverts was estimated by multiplying the dose-length product (DLP) by 2.3 [
      • Vock P.
      CT dose reduction in children.
      ], because the machine uses a 32-cm phantom to evaluate the BSA. The effective radiation dose delivered during a chest CTA was calculated using International Commission on Radiological Protection publication 103 to determine the CT conversion factor. Conversion factors were 0.0823 for newborns, 0.0525 for 1-year old infants, 0.0344 for children aged 1–5 years, 0.0248 for children aged 5–10 years, and 0.0147 for children older than 10 years, and were based on a scan tube voltage of 80 [
      • Deak P.D.
      • Smal Y.
      • Kalender W.A.
      Multisection CT protocols: sex- and age-specific conversion factors used to determine effective dose from dose-length product.
      ].

      2.10 Statistical analysis

      Continuous variables are presented as mean and standard deviations (SDs) for normal distribution and tested by t-test or median and interquartile range (IQR) for non-normal distribution and tested by Kruskal-Wallis test; categorical variables are presented as counts and percentages and tested by Chi-square test or Fisher's Exact test. The associations between measured parameters and PH were evaluated by logistic regression and baseline characteristics that were significantly different between the PH group and non-PH group were selected into multivariate logistic regression for adjustment. In addition, the receiver operating characteristic (ROC) curve was used to find the best cut-off point for parameters measured by Youden's index. Interrater reliability (IRR) was assessed using Kappa statistics. IRR was poor, fair, good, and excellent for Cohen's Kappa values from 0.0 to 0.2 indicating slight agreement, 0.21 to 0.40 indicating fair agreement, 0.41 to 0.60 indicating moderate agreement, 0.61 to 0.80 indicating substantial agreement, and 0.81 to 1.0 indicating almost perfect or perfect agreement, as previously described [
      • Hallgren K.A.
      Computing inter-rater reliability for observational data: an overview and tutorial.
      ]. The intrarater reliability was evaluated on the basis of test–retest reliability, and a Pearson correlation coefficient of >0.7 indicated good consistency [
      • Bland J.M.
      • Altman D.G.
      Statistical methods for assessing agreement between two methods of clinical measurement.
      ]. All statistical analyses were two-tailed and were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA). A p value of <0.005 was established as statistical significance.

      3. Results

      3.1 Characteristics of the study population

      A total of 44 children with CHD were included, and they were divided into two groups, the PH (n = 22) group and non-PH (n = 22) group, on the basis of PASP > 40 mm Hg. The patients' demographic and clinical characteristics are shown in Table 1. The study population consisted of 21 females and 23 males. The median age of PH and non-PH groups was 36 months and 1 month, respectively (p < 0.05) and the distribution of patent ductus arteriosus (PDA) was significantly different between groups (p < 0.05). PASP, D-RVD-BSA, D-LVD-BSA, D-RVCSA-BSA, S-RVD-BSA and S-LVD-BSA were significantly higher in the PH group (all p < 0.05), while S-RVCSA-BSA, S-LVCSA-BSA and S-SEI were lower in the PH group than in the non-PH group (all p < 0.05) (Table 1).
      Table 1Characteristics of the study population.
      VariableNon-PH group

      N = 22
      PH group

      N = 22
      p-Value
      Age, months36 (8, 84)1 (0.13, 5)<0.0001
      Kruskal-Wallis test.
      p < 0.05.
      Sex
       Female11 (50%)10 (45.45%)0.76
      Chi-square test.
       Male11 (50%)12 (54.55%)
      Diagnosis
       ASD7 (31.82%)13 (59.09%)0.07
      Chi-square test.
       VSD10 (45.45%)16 (72.73%)0.07
      Chi-square test.
       CoA3 (13.64%)4 (18.18%)1.00
      Fisher's Exact test.
       PDA2 (9.09%)10 (45.45%)0.01
      Chi-square test.
      p < 0.05.
       TAPVR/PAPVR2 (9.09%)3 (13.64%)1.00
      Fisher's Exact test.
      PASP25.45 ± 8.4458.41 ± 10.39<0.0001
      t-Test.
      p < 0.05.
      D-RVD-BSA5.02 ± 1.869.22 ± 2.87<0.0001
      t-Test.
      p < 0.05.
      D-LVD-BSA5.57 ± 2.388.77 ± 2.38<0.0001
      t-Test.
      p < 0.05.
      D-RVCSA-BSA18.79 ± 6.5223.45 ± 7.870.04
      t-Test.
      p < 0.05.
      D-LVCSA-BSA21.07 (18.84, 25.15)22.39 (19.64, 31.34)0.36
      Kruskal-Wallis test.
      D-RVD/LVD0.88 (0.74, 1.08)1.01 (0.85, 1.13)0.26
      Kruskal-Wallis test.
      D-RVCSA/LVCSA0.71 (0.55, 1.21)0.83 (0.66, 0.98)0.28
      Kruskal-Wallis test.
      D-SEI0.81 ± 0.110.75 ± 0.160.18
      t-Test.
      D-MPA/Ao1.13 (1.08, 1.24)1.56 (1.26, 1.72)0.0001
      Kruskal-Wallis test.
      p < 0.05.
      S-RVD-BSA4.62 ± 1.588.21 ± 2.39<0.0001
      t-Test.
      p < 0.05.
      S-LVD-BSA4.55 ± 2.146.87 ± 1.810.0004d
      p < 0.05.
      S-RVCSA-BSA8.98 (5.68, 12.25)3.99 (3.44, 5.08)0.001
      Kruskal-Wallis test.
      p < 0.05.
      S-LVCSA-BSA8.45 (6.06, 13.85)4.20 (2.48, 5.26)0.0002
      Kruskal-Wallis test.
      p < 0.05.
      S-RVD/LVD0.96 (0.89, 1.19)1.07 (0.99, 1.32)0.05
      Kruskal-Wallis test.
      S-RVCSA/LVCSA0.86 (0.74, 1.19)0.89 (0.81, 1.29)0.31
      Kruskal-Wallis test.
      S-SEI0.90 ± 0.090.79 ± 0.190.02
      t-Test.
      p < 0.05.
      S-MPA/Ao1.19 (1.10, 1.26)1.66 (1.46, 1.84)<0.0001
      Kruskal-Wallis test.
      p < 0.05.
      Continuous variables are shown as median and interquartile range for non-normal distribution or mean and standard deviation (SD) for normal distribution; categorical variables are shown as count and percentage.
      PH: pulmonary hypertension, ASD: atrial septal defect, VSD: ventricular septal defect, CoA: coarctation, PDA: patent ductus arteriosus, TAPVR/PAPVR: total/partial anomalous pulmonary venous return, PASP: pulmonary arterial systolic pressure, D: diastolic, S: systolic, BSA: body surface area, RVD: right ventricular diameter, LVD: left ventricular diameter, RVCSA: right ventricular cross-sectional area, LVCSA: left ventricular cross-sectional area, SEI: septal eccentricity index; MPA/Ao: main pulmonary artery/ascending aorta ratio.
      a Kruskal-Wallis test.
      b Chi-square test.
      c Fisher's Exact test.
      d t-Test.
      low asterisk p < 0.05.

      3.2 ECG-CTA-gated image parameters and associations with pulmonary pressures

      As shown in Fig. 2, the D-RVD-BSA or S-RVD-BSA and PASP correlated significantly with PASP levels (R2 = 0.38 and 0.44, respectively, all p < 0.05). Logistic regression of the association between measured parameters and PH are shown in Table 2. Results of univariate analysis showed that patients with higher RVD-BSA [OR (95% CI) diastolic: 2.55 (1.45–4.48); systolic: 3.92 (1.70–9.05)] and LVD-BSA [OR (95% CI) diastolic: 1.79 (1.26–2.56); systolic: 1.93 (1.26–2.97)] had higher risk of PH (all p < 0.05). Patients with higher S-RVCSA-BSA (OR = 0.77, 95% CI = 0.64–0.94), S-LVCSA-BSA (OR = 0.83, 95% CI = 0.70–0.97), or S-SEI (OR = 0.77, 95% CI = 0.001–0.48) had lower risk of PH (all p < 0.05) (Table 2). However, results of multivariate analysis only remained significant in RVD-BSA [aOR (95% CI) diastolic: 2.76 (1.23–6.23); systolic: 6.15 (1.72–22.06)] after adjusting for age and PDA (all p < 0.05, Table 2).
      Fig. 2
      Fig. 2Correlations between D-RVD-BSA, S-RVD-BSA and PASP in all patients. Scatter plot showing relationship between D-RVD-BSA and PASP (A), and between S-RVD-BSA and PASP.
      Table 2Associations between measured parameters and PH.
      VariableUnivariateMultivariate
      Models were adjusted for age and PDA.
      OR (95% CI)aOR (95% CI)
      D-RVD-BSA2.55 (1.45–4.48)2.76 (1.23–6.23)
      D-LVD-BSA1.79 (1.26–2.56)1.44 (0.93–2.24)
      D-RVCSA-BSA1.10 (1.00–1.22)1.09 (0.95–1.24)
      D-LVCSA-BSA1.04 (0.96–1.12)1.04 (0.95–1.14)
      D-RVD/LVD4.38 (0.54–35.39)2.12 (0.27–16.87)
      D-RVCSA/LVCSA2.03 (0.58–7.07)1.51 (0.38–5.97)
      D-SEI0.04 (<0.001–4.66)0.08 (<0.001–13.19)
      D-MPA/Ao39.20 (2.62–586.80)12.34 (0.59–257.02)
      S-RVD-BSA3.92 (1.70–9.05)6.15 (1.72–22.06)
      S-LVD-BSA1.93 (1.26–2.97)1.37 (0.78–2.41)
      S-RVCSA-BSA0.77 (0.64–0.94)1.03 (0.79–1.35)
      S-LVCSA-BSA0.83 (0.70–0.97)1.20 (0.85–1.69)
      S-RVD/LVD6.24 (0.60–64.91)6.60 (0.32–135.26)
      S-RVCSA/LVCSA1.56 (0.50–4.87)1.41 (0.36–5.58)
      S-SEI0.002 (<0.001–0.48)0.002 (<0.001–0.51)
      S-MPA/Ao136.62 (7.33–>999)74.51 (2.06–>999)
      PH: pulmonary hypertension, OR: odds ratio, CI: confidence interval, D: diastolic, S: systolic, BSA: body surface area, RVD: right ventricular diameter, LVD: left ventricular diameter, RVCSA: right ventricular cross-sectional area, LVCSA: left ventricular cross-sectional area, SEI: septal eccentricity index; MPA/Ao: main pulmonary artery/ascending aorta ratio.
      Number in bold indicate statistically significant results, p < 0.05.
      a Models were adjusted for age and PDA.
      The cut-off value of D-RVD-BSA and S-RVD-BSA for prediction of PH by ROC curve analysis was determined. As shown in Fig. 3, the area under the curve (AUC) of D-RVD-BSA was 0.907 and the AUC of S-RVD-BSA was 0.917 (all p < 0.05). After determining the best cut-off point of RVD-BSA, logistic regression showed that patients with D-RVD-BSA over 6.86 had significantly higher risk of PH (OR = 45, 95% CI = 7.34–275.76) and the result remained significant after adjustment (aOR = 23.52, 95% CI = 2.89–191.03); patients with S-RVD-BSA over 5.87 had significantly higher risk of PH (OR = 45, 95% CI = 7.34–275.76) and the result remained significant after adjustment (aOR = 31.14, 95% CI = 2.75–352.85) (Table 3).
      Fig. 3
      Fig. 3ROC curves for predicting pulmonary hypertension with D-RVD-BSA or S-RVD-BSA. The AUCs of the D-RVD-BSA (A) or S-RVD-BSA (B) for predicting pulmonary hypertension were 0.907 and 0.917, respectively.
      Table 3Associations between right ventricular diameter and PH.
      VariableUnivariateMultivariate
      Models were adjusted for age and PDA.
      OR (95% CI)aOR (95% CI)
      D-RVD-BSA
       <6.8611
       ≥6.8645 (7.34–275.76)23.52 (2.89–191.03)
      S-RVD-BSA
       <5.8711
       ≥5.8745 (7.34–275.76)31.14 (2.75–352.85)
      D-MPA/Ao
       <1.1811
       ≥1.1816.89 (3.63–78.53)11.45 (1.85–70.79)
      S-MPA/Ao
       <1.3211
       ≥1.3240.11 (7.17–224.45)NA
      PH: pulmonary hypertension, OR: odds ratio, CI: confidence interval, D: diastolic, S: systolic, BSA: body surface area, RVD: right ventricular diameter; MPA/Ao: main pulmonary artery/ascending aorta ratio.
      NA, Odds ratio could not be computed due to large odds ratio, aOR (95% CI) = >999 (<0.001–>999).
      Number in bold indicate statistically significant results, p < 0.05.
      a Models were adjusted for age and PDA.

      3.3 Radiation dose estimations

      The median CT dose index was 1.10 ± 0.84 mGy during prospective ECG-gated acquisition of each scan. The average DLP provided by the CT system for estimating the radiation dose of one phase was 18.51 ± 21.67 mGy∗cm. The average effective radiation dose of two phases in 44 patients was 2.82 ± 1.17 mSv (1.42 ± 0.57 mSv for one phase).

      4. Discussion

      CHD is one of the leading etiologies of pediatric PH [
      • Engelfriet P.M.
      • Duffels M.G.
      • Moller T.
      • Boersma E.
      • Tijssen J.G.
      • Thaulow E.
      • et al.
      Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro Heart Survey on adult congenital heart disease.
      ,
      • Diller G.P.
      • Gatzoulis M.A.
      Pulmonary vascular disease in adults with congenital heart disease.
      ,
      • McLaughlin V.V.
      • Archer S.L.
      • Badesch D.B.
      • Barst R.J.
      • Farber H.W.
      • Lindner J.R.
      • et al.
      ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association.
      ]. Recently, MDCT has been used increasingly for imaging patients with CHD because it provides high-quality three-dimensional images enabling evaluation of the complex heart structure and delivers a reasonable radiation dosage, especially in prospective ECG-gated CTA model (step-and-shoot mode) [
      • Lim S.
      • Lee H.
      • Lee S.J.
      • Kim J.K.
      • Suh J.
      • Lee E.H.
      • et al.
      CT signs of right ventricular dysfunction correlated with echocardiography-derived pulmonary arterial systolic pressure: incremental value of the pulmonary arterial diameter index.
      ,
      • Jone P.N.
      • Hinzman J.
      • Wagner B.D.
      • Ivy D.D.
      • Younoszai A.
      Right ventricular to left ventricular diameter ratio at end-systole in evaluating outcomes in children with pulmonary hypertension.
      ,
      • Grosse A.
      • Grosse C.
      • Lang I.
      Evaluation of the CT imaging findings in patients newly diagnosed with chronic thromboembolic pulmonary hypertension.
      ]. However, data on CT-based parameters for predicting PH in patients with CHD are scant, and only certain echocardiographic values are currently available [
      • Cantinotti M.
      • Scalese M.
      • Murzi B.
      • Assanta N.
      • Spadoni I.
      • De Lucia V.
      • et al.
      Echocardiographic nomograms for chamber diameters and areas in Caucasian children.
      ]. In the present study, pediatric patients with CHD who had increased D-RVD-BSA or S-RVD-BSA had higher risk of PH. In particular, the cutoff values of 6.86 and 5.87 for the diastolic and systolic BSA-modified RVDs had higher sensitivities and specificities to predict the occurrence of PH in these patients. This suggests that D-RVD-BSA and S-RVD-BSA may be useful biomarkers for predicting PH in children with CHD.
      In echocardiographic assessment of the right heart in adults, an RV basal dimension with an upper reference limit of 4.2 cm was determined to indicate RV dilation [
      • Rudski L.G.
      • Lai W.W.
      • Afilalo J.
      • Hua L.
      • Handschumacher M.D.
      • Chandrasekaran K.
      • et al.
      Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography.
      ]. Recommended values of the RV were previously reported in children, with predicted values of measured echocardiographic variables expressed with respect to the body surface area (BSA) [
      • Cantinotti M.
      • Scalese M.
      • Murzi B.
      • Assanta N.
      • Spadoni I.
      • De Lucia V.
      • et al.
      Echocardiographic nomograms for chamber diameters and areas in Caucasian children.
      ]. Compared to these studies, we further found that the cut-off value of diastolic or systolic BSA-modified D-RVD (6.86) or S-RVD (5.87) calculated by prospective ECG-gated CTA imaging is able to accurately predict PH in children with CHD. Of note, the artifact burden was low and the overall image quality was high, which is of particular importance and is among the main reasons we chose to use prospective high-pitch ECG-triggered dual-source CT with low radiation dose. This result also has been demonstrated by Li et al. [
      • Li T.
      • Zhao S.
      • Liu J.
      • Yang L.
      • Huang Z.
      • Li J.
      • et al.
      Feasibility of high-pitch spiral dual-source CT angiography in children with complex congenital heart disease compared to retrospective-gated spiral acquisition.
      ], who concluded that the intra-cardiac and extra-cardiac malformation, coronary artery origin, and course malformation can be visualized clearly using a high-pitch ECG-triggered dual-source CT with a low radiation dose and good image quality in patients with CHD.
      CT has an important role in the diagnosis and follow-up of CHD, although it is used less frequently than echocardiography and cardiac magnetic resonance imaging (CMR) because of radiation and contrast exposure. However, CT is the choice of imaging for patients with limited echocardiographic windows, claustrophobia when undergoing CMR, poor compliance, implantation of a pacemaker or implantable cardioverter defibrillator, or large metallic prostheses causing extensive artifacts on CMR. The present study confirms the potential of using parameters measured on prospective ECG-gated cardiac CTA for predicting pediatric PH with respect to the reference standard of the echocardiography-derived PASP. Although the definition of PH continues to be based on invasive hemodynamic measurement of mean pulmonary artery pressure (mPAP) obtained through right heart catheterization, mPAP can be calculated from the estimated PASP derived from echocardiography according to the formula mPAP [
      • Chemla D.
      • Castelain V.
      • Provencher S.
      • Humbert M.
      • Simonneau G.
      • Hervé P.
      Evaluation of various empirical formulas for estimating mean pulmonary artery pressure by using systolic pulmonary artery pressure in adults.
      ].
      Compared to retrospective ECG-gated computed tomography (CT), non-ECG-gated scanning technique is usually applied in CTA studies with low radiation dose in pediatric patients with CHD [
      • Liu Y.
      • Li J.
      • Zhao H.
      • Jia Y.
      • Ren J.
      • Xu J.
      • et al.
      Image quality and radiation dose of dual-source CT cardiac angiography using prospective ECG-triggering technique in pediatric patients with congenital heart disease.
      ,
      • Goo H.W.
      • Park I.S.
      • Ko J.K.
      • Kim Y.H.
      • Seo D.M.
      • Yun T.J.
      • et al.
      Visibility of the origin and proximal course of coronary arteries on non-ECG-gated heart CT in patients with congenital heart disease.
      ,
      • Tsai I.C.
      • Lee T.
      • Chen M.C.
      • Fu Y.C.
      • Jan S.L.
      • Wang C.C.
      • et al.
      Visualization of neonatal coronary arteries on multidetector row CT: ECG-gated versus non-ECG-gated technique.
      ]. The present study exhibited that the average effective radiation dose of two phases in 44 patients was 2.82 mSv (1.42 mSv for one phase). However, this appears to be higher than previously reported sub-millisievert radiation doses [
      • Liu Y.
      • Li J.
      • Zhao H.
      • Jia Y.
      • Ren J.
      • Xu J.
      • et al.
      Image quality and radiation dose of dual-source CT cardiac angiography using prospective ECG-triggering technique in pediatric patients with congenital heart disease.
      ], which we attribute to our use of rigorous conversion and correction factors in CT radiation estimation. However, the mean CT dose index and DLP were 1.10 mGy and 18.51 mGy∗cm, respectively; these values are quite similar to radiation data from other prospective ECG-gated acquisitions [
      • Grosse A.
      • Grosse C.
      • Lang I.
      Evaluation of the CT imaging findings in patients newly diagnosed with chronic thromboembolic pulmonary hypertension.
      ].
      The main pulmonary artery/ascending aorta ratio (MPA/Ao) on CT has been reported to be associated with PAH in children [
      • Liu Y.
      • Li J.
      • Zhao H.
      • Jia Y.
      • Ren J.
      • Xu J.
      • et al.
      Image quality and radiation dose of dual-source CT cardiac angiography using prospective ECG-triggering technique in pediatric patients with congenital heart disease.
      ]. Those authors reported the diameter ratio of the main pulmonary artery to the ascending aorta on the same plane of axial view in both systolic and diastolic phases, showing high correlation between PASP and S-MPA/Ao and D-MPA/Ao. In the present study, results showed that diastolic- and systolic-MPA/Ao ratios were associated with PASP (AUCs were 0.835 and 0.886, respectively (Supplementary Fig. 4)), which was similar to the results of the above-cited study. Having obtained similar results using our images with the reported parameters from the literature further validates our novel findings for RVD-BSA.
      Some limitations of the present study have to be considered. First, we excluded CHD patients with pulmonary stenosis or RVOT obstruction. Therefore, the findings of this study cannot be extrapolated to a general CHD population. Second, ECG-gated CTA protocols may have suboptimal quality related to various factors: different contrast enhancement in adjacent slice slabs, step artifacts due to movement in noncompliant patients, and respiratory artifacts in patients with poor breath holding [
      • Young C.
      • Taylor A.M.
      • Owens C.M.
      Paediatric cardiac computed tomography: a review of imaging techniques and radiation dose consideration.
      ]. Third, the data acquisition windows in our cases are 70% and 30% of the R-R interval for diastole and systole, respectively, which did not represent the real situation in end-systole and end-diastole. Finally, although CT scans are not used in the longitudinal assessment of PH in children because of radiation exposure, functional CT parameters can provide quantitative information to supplement anatomic evaluations.

      5. Conclusion

      In children with CHD, measurements of diastolic and systolic BSA-modified RVDs using prospective ECG-gated CTA are non-invasive markers of PH. BSA-modified D-RVD of 6.86 or BSA-modified S-RVD of 5.87 may be used to distinguish PH over 40 mm Hg in children with CHD.
      The following are the supplementary data related to this article.
      • Supplementary Fig. 1

        Measurement of ventricular diameter through ECG-gated cardiac CTA. Based on user-selected reference points for the location of the valvular annulus, the software renders a three-dimensional estimate of the ventricular cavity (A → B). The observer then visually reviews and vertically cuts the left ventricular wall and reconstructs the two-chamber view (B → C). The cutting plane is moved until the papillary muscle is no longer visible and the four-chamber view is reconstructed. RV and LV dimensions are measured by identifying the maximal distance between the ventricular endocardium and the interventricular septum, perpendicular to the long axis (C → D).

      • Supplementary Fig. 2

        Measurements of ventricular CSA through ECG-gated cardiac CTA. Once the ventricles are properly segmented in the four-chamber view, the software manually calculates the ventricular CSA for both the RV and LV.

      • Supplementary Fig. 3

        Measurement of eccentricity index through ECG-triggered cardiac CTA. Based on user-selected reference points for the location of the valvular annulus, the software renders a three-dimensional estimate of the ventricular cavity (A → B). The observer then visually reviews and vertically cuts the left ventricular wall and reconstructs the two-chamber view (B → C). The cutting plane is adjusted at the mitral chordal level, and the SEI is obtained as a ratio of the distance between the septal–lateral wall and the anterior–posterior wall measured in the short-axis view (C → D).

      • Supplementary Fig. 4

        ROC curves for predicting pulmonary hypertension with D-MPA/Ao or S-MPA/Ao. The AUC of the D-MPA/Ao (A) or S-MPA/Ao (B) for predicting pulmonary hypertension was 0.835 and 0.886, respectively.

      Funding source

      This research was not funded by any grant from agencies in the public, commercial, or not-for-profit sector.

      Declaration of competing interest

      All authors declare that there are no conflicts of interest in this study and that this work received no funding.

      Acknowledgments

      We would like to thank Convergence CT for providing English editing to improve English grammar and language usage. The research was supported by National Cheng Kung University Hospital ( NCKUH-10803025 ).

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