Normative Computed Tomography Angiography Values of the Aortic Root, Aorta and Aortic arch in Children

Purpose Normative values for intracardiac and extracardiac vascular structures help in understanding normal growth and changes over time in children; this normative data are not currently available for ECG-gated Computed Tomography Angiography (CTA). We sought to establish ECG-gated CTA derived normative values for the aortic root, aorta and aortic arch in children. Methods and Results Aortic root, ascending aorta, aortic arch, and descending aorta were measured in systole and diastole in 100 subjects who had ECG-gated CTA at our center between January 2015 through December 2020 and met our inclusion criteria. The allometric exponent (AE) for each parameter was derived, and the parameter/body surface areaAE (BSAAE) was established using the previously described methods. Using this data, normalized mean, cross-sectional area, and standard deviation were calculated. Z-score curves were plotted in relation to the BSA for all measurements. Conclusion Our study reports systolic and diastolic ECG-gated CTA Z-scores along with normative curves in relation to BSA for the aortic root, aorta and aortic arch in children.


Introduction
Overall survival and outcomes have improved in patients with congenital heart disease due to signi cant advances in the diagnosis, management, and treatment 1 2 .Cardiac imaging including echocardiography (echo), cardiac ECG-gated computed tomography angiography (CTA), and cardiac Magnetic resonance imaging (CMR) play a vital role in the diagnosis and follow-up of patients with congenital heart defects and patients with connective tissue disease (Marfan, Ehler-Danlos, Loeys-Dietz syndrome etc) 3 4 5 6 7 .
Normative data for intracardiac and extracardiac vascular structures in the pediatric population are available for echo, CMR and non ECG-gated CTA 8 9 10 11 .As a result, imagers tend to interpret the CTA aortic measurements with known echo or CMR normative data, this is not ideal due to the inherent variation of the imaging modalities.
The utility of CTA is gaining acceptance in pediatric cardiology with improvements in scanning techniques, advances in radiation reduction, ease of access, and its ability to limit anesthesia exposure in young children due to fast scan times 6,12 .Cross-sectional imaging with CTA and CMR has added bene t in advanced planning for interventional procedures, creation of virtual or 3D models, overlaying with angiography to reduce radiation dose during an intervention, etc [13][14][15][16] .En face measurements using Population: All children less than or equal to 18 years of age, who underwent ECG-gated cardiac CTA at our institution from January 2015 to December 2020 who met the inclusion criteria as listed in Table 1 were identi ed, those meeting the exclusion criteria were removed from the nal analysis.The diagnosis and indication of the CTA for the included subjects are listed in Table 2.As cardiac CTA is not routinely performed in normal subjects, we broadly de ned subjects without cardiac involvement as "normal".Children with vascular rings (double aortic and right aortic arches) were also included in this study.For vascular ring subjects only the aortic root, ascending aorta and descending abdominal aortic measurements away from the vascular ring were recorded as normal, in this way we avoided the area of pathology.As such the number of subjects has been lower compared to an echo or CMR study with • Small patent foramen ovale • Any CHD other than listed in the inclusion criteria.
• Aortic valve disease • Diagnosed connective tissue disorder (Marfan, Ehler-Danlos, etc.) • Rheumatic heart disease Patient selection, preparation, and contrast medium: All patients were referred to our imaging center by a pediatric cardiologist for further evaluation.An initial screen was performed by an attending imaging cardiologist prior to cardiac CTA after reviewing echocardiographic information, patient medical records, and available clinical and diagnostic information.Those deemed candidates for CTA followed our institutional imaging protocol.Subjects younger than 6 weeks often underwent feed and swaddle techniques to minimize the need for sedation.Subjects between 6 weeks and 6 years were individualized based on the imaging goal, if anesthesia was needed, deep sedation without intubation was preferred for subjects with vascular rings.In subjects with a feed and swaddle approach image acquisition and timing were geared toward the clinical question.Some of these subjects had diagnostic studies but the image quality may not have been adequate for our study purpose as such they were excluded.Subjects less than 6 years requiring coronary artery evaluation were often anesthetized and intubated for better heart rate and respiratory control to avoid motion artifacts 24 .The location of the peripheral intravenous (PIV) access was determined by the imaging question.To evaluate for the aortic arch abnormalities, a foot PIV was preferred for contrast injection.Iso-osmolar, nonionic, and water-soluble agents (Iodixanol, Visipaque™ 320 mg iodine/ml) were used for all the examinations 25 .The total contrast dose was 1.5-2 ml/kg of body weight.The contrast medium was administered using a dual-head power injector at an injection rate of 0.8-1.2ml/s for a 24G PIV.The injection rate is increased based on the size of the PIV up to 4-6.5 ml/s 12,26 .A bolus of isotonic saline solution was administered after contrast to reduce high-density contrast (streak) artifact.
Automated bolus tracking technique was used with reference cardiovascular structure being monitored at near real-time until predetermined threshold opaci cation of 120-150 Houns eld units was achieved at reference level.A scan delay of 4-5 seconds was often used for image acquisition 27 .
Cardiac CTA technique: During the study period, different generations of Siemens CT scanners were used to perform these studies.These include SOMATOM AS 128, SOMATOM de nition edge, and SOMATOM Force Dual-source CT (Siemens Healthineers).Studies were performed according to our institutional protocol using a tube voltage of 70-100 kV and tube current auto modulation (CareDose4D, Siemens Healthineers), a slice thickness of 0.6 mm 9,26,28 .Retrospective electrocardiography (ECG)-gated acquisition was performed when ventricular volume/function and coronary artery evaluation were needed.The prospective ECGtriggered technique was used to delineate vascular anatomy 11 .Images were reconstructed with a slice thickness of 0.6 mm and an increment of 0.4-0.6 mm 29 .
Images acquired when the aortic valve was open were included under systole, usually between 30 and 40% RR interval.and the images acquired during 70-80% RR interval were included under diastole.Subjects who underwent retrospectively ECG-gated CTA had both systolic and diastolic images.
Prospectively ECG-gated CTA images were acquired either in systole or diastole based on the subject's heart rate as per the machine algorithm and imager preference to minimize motion artifact.All studies were performed with an imaging cardiologist present during the scan.
Image Post-processing: All measurements were performed on a cardiovascular imaging workstation (Circle CVI42; Circle Cardiovascular Imaging Inc. Alberta, Canada) after studies were anonymized.All images were visualized in axial, sagittal, and coronal planes with a window (600-900) and a level (250-350) settings.Double oblique planes using multiplanar reformatting were performed to measure aortic root, sinotubular junction (STJ), ascending aorta (AAO) at the level of the branch pulmonary artery, proximal (PTA) and distal transverse arch (DTA), aortic isthmus (IS), and descending aorta (DAO) at the level of the diaphragm 17,18,30 .As mentioned arch measurements for vascular ring subjects were not performed to avoid errors.Maximum, minimum, and mean diameters and cross-sectional area are measured for all the parameters except for the aortic root.(Fig. 1).For the aortic root, three measurements were made at mid-sinus level at their maximum dimensions.Cusps were named by the expected coronary artery origin, and commissures go along with them 31 .Aortic root measurements for this study are named as follows (Fig. 2).
A-Right cusp to left/non-coronary commissure diameter B-Left cusp to non-coronary/right commissure diameter C-Non-coronary cusp to right/left commissure diameter.
The measurements were categorized as either systole or diastole as described above.Aortic measurements were performed at the following levels: ascending aorta was measured at the level of the right pulmonary artery/ bifurcation of pulmonary arteries 18,20 , proximal transverse arch was measured immediately after the rst branch of aorta, distal transverse arch was measured before the left subclavian artery, isthmus was measured after the last aortic branch.Descending Aorta was measured at the level of the diaphragm 18 .

Statistical analysis:
Data was expressed as mean ± SD.The measure of the vessel was indexed to the body surface area (BSA) according to the Haycock formula 32 .The allometric exponent for each parameter was derived by applying the ordinary least squares method in which the natural logarithm of the parameter was regressed on the natural logarithm of BSA 33,34 .This method allows for a nonlinear relationship between the parameter and BSA.Speci cally, the following steps were used.
1.The equation Y = mX b was considered to decide the potentially nonlinear relationship between a parameter and BSA.Y denoted the parameter, X denoted BSA, and b was the AE to be estimated.2. After taking the natural log, a linear regression formula was obtained: ln(Y) = ln(m) + bln(X), where ln(Y) was the dependent variable and ln(X) was the independent variable.
BSA.The regression line was plotted, and R 2 was calculated.A at line and a small R 2 indicate no residual relationship.Pearson correlation coe cient and the corresponding P value were determined.A correlation close to zero and a P-value ≥ 0.05 also indicate no residual relationship.
We checked the normality of the indexed parameter using the Shapiro-Wilk test and reported µ ± where µ and denoted the mean and SD of the indexed parameter.Last, we plotted non-indexed parameters against BSA with lines representing the mean, ± 1, ± 2, and ± 3 SDs of the mean based on the relationship that the non-indexed parameter followed a normal distribution with a mean of µBSA AE and SD of BSA AE .
Interobserver and intraobserver variability were assessed using the intraclass correlation coe cient in a subset of 50 subjects.All analyses were conducted using R version 4.0.5 (March 2021).

Patient characteristics:
Out of 628 patients who underwent CTA at our institution during the study period, 100 children met the inclusion criteria and were analyzed.The mean age and BSA of the subjects were 5.3 ± 6.1 years (range 0-18 years) and 0.8 ± 0.68 m 2 (range 0.16-2.8m 2 ) respectively.Among the subjects, 56% were male (Table 3).The majority (71%) of our subjects were young with a BSA < 1 m 2 .The most common nding on the CTA was structurally normal heart (n = 29), followed by right aortic arch with aberrant left subclavian artery (n = 25), and coronary anomaly (n = 21) as shown in Table 2. Normative values: The normalized mean diameters (mm), cross-sectional area (mm 2 ), and standard deviation in systole and diastole are shown in Tables 4, 5. Based on the results in these tables, we can calculate the Z-score of a measurement for a given BSA using the reported AE, mean, and SD of that parameter: The Z-score plots for systolic and diastolic aortic root diameters and their means are shown in Figs. 3,  and 4. The Z-score plots for systolic and diastolic diameters, mean diameters and cross-sectional areas of the aortic structures are shown in Figs. 5, 6, 7 and 8 respectively.As expected systolic diameters were 6-11% larger and systolic cross-sectional areas were 13-20% larger compared to diastolic measures.Aortic root systolic measures were 5% larger than the diastolic measures.

Reproducibility:
There was an excellent inter and intraobserver agreement (> 0.92) for both systolic and diastolic measurements (Tables 6, 7) indicating excellent reproducibility of our method.

Discussion
We report normative systolic, diastolic diameters, cross sectional areas along with Z-scores and normative curves for the aorta, aortic root and aortic arch for ECG-gated cardiac CTA in children younger than 18 years.We report maximum, minimum, and mean diameters as well as the cross-sectional areas for these structures.Normative values in children exist for echo, CMR, and non ECG -gated CTA but are lacking for ECG-gated-CTA [35][36][37] .Few non-ECG-gated CTA studies reported normative measurements so far.Akay et al. 20 used single axial measurement with respect to patient age, sex and T-vertebral body size.Bayindir et al. 19 used single measurements from standard axial imaging planes as well.These measurements did not take the patient size into account; as such, the in uence of growth and body size in a patient cannot be assessed.This methodology can also be challenging especially in patients with congenital heart defects, heterotaxy, etc. where a single-plane measurement may not be practical.
Hegde et al. 18 reported aortic measurements using the double-oblique method using CTAs performed mostly in oncology, chest pain and trauma patients (42%, 16% and 10% respectively); their measurement technique was similar to our study.However, they have not reported cross sectional areas or used ECGgated CTAs which the authors have recognized as a limitation.Their data was modeled using a natural log-transformed response variable.
En face measurements of the aorta provide an accurate assessment of the structure of interest 17 .
Cardiac CTA is gaining acceptance in congenital cardiology to better evaluate vascular structures due to the improvements in scanning techniques, radiation reduction, ease of access, fast scan times, and reduced need for anesthesia in young children 6,28 .
Our study is also unique in reporting both systolic and diastolic normative aortic values; our study con rms larger systolic parameters compared with diastolic measures as was previously described by an angiographic study 38 .
The cross-sectional area along with the mean diameter may have real-world applicability as the structure of interest can be assessed in any non-standard plane.This is especially important in patients with congenital heart defects where a vascular structure may not be in a normal orientation.
Deriving normative values and Z-scores can be achieved by various methods and there is signi cant variation among Z-scores derived from each method [39][40][41][42] .We chose the previously described and validated method of using BSA as an expression of body size and linear regression for the relationship between body growth and cardiovascular dimensions 43,44 21,33,45-47 .Cardiovascular allometry is de ned as the relative growth of cardiac structure in relation to somatic growth.Identifying a correct allometric relationship and model for a structure is important for its interpretation and clinical application 34,43 .
Multiple authors have advocated the use of an allometric model to identify a true indexing method of a physiologically dependent variable and this method has been widely used for various echo Z-score calculators that are in current clinical use [33][34][35]43,44 .
Recruiting normal children for a CTA study is ethically not possible due to radiation exposure, need for sedation/anesthesia, and contrast use.It is not uncommon to identify normal subjects who undergo cross-sectional imaging for various reasons to be included in a study.Prior CMR and CTA studies to derive normative values for the aorta and pulmonary arteries have included children with a history of malignancy 22,23 .We have been diligent to include subjects with normal cardiac anatomy, as a result, this data should be close to what is expected for a normal population.Future studies are needed to validate our results with a larger sample.We plan to make our data publicly available.

Limitations:
Our small-sample, retrospective study has inherent limitations due to its design.Generalized applicability across institutions may not be possible, but there is a lack of normative ECGgated-CTA data available at this time.Our data will help kick-start the process of performing a similar study in a multicenter fashion which can help address issues related to a single-center design.Similar goals have been achieved by the Pediatric Heart Network echocardiogram database that published echocardiographic Z-scores, although normative echo Z-scores have been in existence for a few decades.The statistical methodology may have issues with the model of choice, there has been extensive literature on various Z-score models but we felt that our approach is ideal for this study based on extensive prior experience using allometric models in echocardiographic Z-score studies.Our study population was mostly young with 71% having a BSA of less than 1 m 2 , this resulted in less subjects available for the diastolic measurements as the CTA protocols were geared to acquire during systole.We have not reported aortic annulus, descending thoracic aortic measurements, we feel that the abdominal aortic measurements have more clinical signi cance.Our study has not explored the in uence of sex, or race on the Z-scores due to the small sample size, a multicenter design is likely to address this issue.
Our sample has predominantly young children, its applicability to older children and adolescents should be done with caution.

Conclusions
This is the rst pediatric study to report en face normative diameters and cross-sectional areas of the aortic root, ascending aorta and aortic arch in systole and diastole derived using ECG-gated cardiac CTA.This data has potential application for proper diagnosis, risk strati cation, surgical planning, and planning catheter-related interventions for children with congenital heart defects and connective tissue disorders.The real-world applicability of this tool needs careful validation.

Declarations
Funding: Dr. Wen Li's effort is supported by UL1TR003167.
The other authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Figures
Figure 1 Example showing en face measurements of ascending aorta at the level of the pulmonary artery branching using the double oblique method.

Figure 2 Example
Figure 2

Table 3
PTA = 25, DTA = 34, IS = 34 and DAO = 49 respectively) due to the younger age of our study population the CTA imaging protocols are geared towards acquiring the image during the least heart motion to reduce artifacts.As such systolic imaging was common in young children due to fast heart rates.
Systolic measurements for aortic root, STJ, AAO and DAO were available in the majority of our subjects (n > 77).Systolic IS and DTA measurements were available in 50 subjects.Systolic PTA measurement was available in very few subjects (n = 35) due to common origin of the innominate and left carotid artery (n = 15).The Diastolic measurements were available in fewer subjects (root = 37, STJ = 41, AAO = 47, σ σ

Table 4
Maximum, minimum, mean, and area variables with AE, SD in systole.
Max -maximum diameter, Min -minimum diameter, Mean -mean diameter, area -cross-sectional area, N -number of subjects, AE -allometric exponent, SD-standard deviation.Max, Min, and Mean diameters are reported in millimeters, cross-sectional area is reported in square millimeters.STJsinotubular junction.Aortic root: A-Right cusp to left/non-coronary commissure, B-Left cusp to noncoronary/right commissure, C-Non-coronary cusp to right/left commissure.

Table 5
Maximum, minimum, mean, area variables with AE, SD in diastole.
Max-maximum diameter, Min-minimum diameter, Mean -mean diameter, area -cross-sectional area, N-number of subjects, AE -allometric exponent, SD-standard deviation.Max, Min, and Mean diameters are reported in millimeters, cross-sectional area is reported in square millimeters.STJsinotubular junction, STJ -sinotubular junction.Aortic root: A-Right cusp to left/non-coronary commissure, B-Left cusp to non-coronary/right commissure, C-Non-coronary cusp to right/left commissure., where , µ denotes the mean of the indexed parameter, and denotes the SD of the indexed parameter as described in the statistical analysis section.For example, if a subject has an Ascending Aorta Maximum in systole measurement of 17.44 mm and a BSA of 0.6 m 2 , we can derive the Z-score by plugging in the numbers (AE = 0.49, mean = 18.236,SD = 2.079) to the above equations.That is, , and .

Table 6
Inter and intraobserver variability for parameters in systole.

Table 7
Inter and intraobserver variability for parameters in diastole.