Reference Values for Echocardiographic Assessment of the Diameter of the Aortic Root and Ascending Aorta Spanning All Age Categories

Reference Values for Echocardiographic Assessment of the Diameter of the Aortic Root and Ascending Aorta Spanning All Age Categories Laurence Campens, MDa,*, Laurent Demulier, MDb, Katya De Groote, MDc, Kristof Vandekerckhove, MDc, Daniël De Wolf, MD, PhDc, Mary J. Roman, MDd, Richard B. Devereux, MDd, Anne De Paepe, MD, PhDa, and Julie De Backer, MD, PhDa,b Thoracic aortic dilatation requires accurate and timely detection to prevent progression to thoracic aortic aneurysm and aortic dissection. The detection of thoracic aortic dilatation necessitates the availability of cut-off values for normal aortic diameters. Tools to evaluate aortic dimension above the root are scarce and inconsistent regarding age groups. The aim of this study was to provide reference values for aortic root and ascending aortic diameters on the basis of transthoracic echocardiographic measurements in a large cohort of children and adults. Diameters at the level of the sinuses of Valsalva (SoV) and ascending aorta (AA) were assessed with transthoracic echocardiography in 849 subjects (453 females, age range 1 to 85 years, mean 40.1 – 21.3 years) and measured according to published guidelines. Linear regression analysis was applied to create nomograms, as well as equations for upper limits of normal and z-scores. SoV and AA diameters were strongly correlated with age, body surface area (BSA), and weight (r [ 0.67 to 0.79, p <0.001 for all). Male subjects had significantly larger aortic dimensions at all levels in adulthood, even after BSA correction (p £0.004 for all age intervals). Gender-, age-, and BSA-specific upper limits of normal and z-score equations were developed from a multivariate regression model, which strongly predicts SoV and AA diameters (adjusted R2 for SoV [ 0.84 and 0.67 and for AA [ 0.82 and 0.74, for male and female subjects, respectively). In conclusion, this study provides widely applicable reference values for thoracic aortic dilatation screening purposes. Age, BSA, and gender must be taken into account when assessing an individual patient. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;114:914e920) Correctly defining aortic dilatation requires upper limits of normal (ULNs) for aortic diameters. Aortic dilatation is defined as a diameter of 1.96 standard errors of the estimate (SEEs) above the predicted diameter for a specific patient.1 Dilatation of the proximal thoracic aorta, defined as the segment of the aorta between the aortic valve and the brachiocephalic artery, is frequently encountered in distinct pathologies such as heritable aortopathies (e.g., Marfan syndrome and Loeys-Dietz syndrome), Turner syndrome, and bicuspid aortic valve syndrome, but it also occurs in the setting of degenerative aortic disease.2 As dilatation progresses, it confers risk for aortic valve regurgitation and/or aortic dissection, the latter of which is associated with considerable morbidity and mortality.2 Because initially

published nomograms used to predict normal proximal thoracic aortic diameters for body surface area (BSA), age, and/or gender were based on small reference populations with varying age groups, Devereux et al1 recently published reference values for sinuses of Valsalva (SoV) diameters obtained in a large cohort of normal subjects aged 15 to 86 years. Until now, however, very limited 2-dimensional echocardiographic data on the ascending aorta (AA) over a wide age range are available.3,4 With this study, we aimed to provide uniform guidelines for evaluation of the aortic diameters at the SoV and AA on the basis of echocardiographic measurements in a large cohort of children and adults ranging from 1 to 85 years of age. Methods

a

b

Center for Medical Genetics and Departments of Cardiology and Pediatric Cardiology, Ghent University Hospital, Ghent, Belgium; and d Division of Cardiology, Weill Cornell Medical College, New York, New York. Manuscript received March 28, 2014; revised manuscript received and accepted June 12, 2014. Dr. De Backer is a senior clinical researcher supported by the Flanders Research Fund, Brussels, Belgium. Dr. De Paepe is a holder of a Methusalem Grant (01M01108) from the Ghent University Special Research Fund, Ghent, Belgium. See page 919 for disclosure information. *Corresponding author: Tel: þ32-93325187; fax: þ32-93324970. E-mail address: [email protected] (L. Campens). c

0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.06.024

Patients who underwent routine cardiovascular checkups in the context of family screening for genetic disease, preoperative evaluation for noncardiovascular surgery, cardiovascular evaluation to obtain permission for sports activities, or exclusion of pericarditis or endocarditis, as well as patients under follow-up at the outpatient clinic of the cardiology department for various reasons, other than aortopathy, requiring cardiac ultrasound (previous chemotherapy, rheumatic disorders, arrhythmia, or coronary artery disease), were included in this analysis. Patients with bicuspid aortic valves, significant valvular disease, or evidence of connective tissue www.ajconline.org

Miscellaneous/Reference Values for the Proximal Aorta

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Table 1 Body size parameters, age, blood pressure and aortic dimensions for males and females Variable

Total (N ¼ 849)

Age (years) Systolic BP (mmHg) Diastolic BP (mmHg) Height (cm) Weight (kg) Body surface areaDB (m2) Body surface areaH (m2) Body mass index (kg/m2) Annulus (mm) Sinuses of Valsalva (mm) Sinotubular junction (mm) Ascending aorta (mm)

40.1 129.5 72.3 164.5 64.5 1.7 1.7 23.1 19.6 29.7 25.4 27.1

           

21.3 17.3 11.2 19.5 19.5 0.4 0.4 4.8 3.0 5.4 5.1 5.5

Males <15y (N ¼ 80) 8.5 110.3 63.3 132.9 31.1 1.1 1.1 16.6 15.6 21.6 17.3 18.9

           

3.6 13.3 10.5 25.7 14.3 0.3 0.3 2.7 2.9 3.7 3.0 2.9*

Females 15y (N ¼ 316) 45.2 134.3 73.7 177.4 77.7 1.9 2.0 24.7 21.8 33.4 28.5 30.0

           

18.1 14.8† 11.7 8.3† 13.6† 0.2† 0.2† 4.1* 2.1† 3.8† 3.7† 4.3†

<15y (N ¼ 53) 8.1 108.3 63.4 130.7 30.3 1.0 1.0 16.7 14.8 20.6 16.8 17.8

           

3.6 13.6 9.0 25.4 14.0 0.3 0.3 2.6 2.5 3.7 3.2 3.2*

15y (N ¼ 400) 46.6 129.1 72.6 165.0 65.3 1.7 1.7 24.0 19.2 29.4 25.5 27.7

           

17.4 17.2† 10.4 7.2† 11.7† 0.2† 0.2† 4.2* 1.9† 3.4† 3.2† 3.9†

Body surface areaDB ¼ BSA calculated with the Dubois and Dubois formula; Body surface areaH ¼ BSA calculated with the Haycock formula; BP ¼ blood pressure. Data are presented as mean  standard deviation. * p-value <0.05. † p-value <0.001 for the difference between males and females.

Figure 1. Line chart of aortic dimensions (in millimeters) and body size parameters (height [in centimeters], weight [in kilograms], and BSA [in kilograms per square meter]) as a function of age. *Line represents BSADB and BSAH as a function of age.

disorders, such as Marfan syndrome, were excluded. All subjects underwent echocardiographic examinations at the pediatric or adult cardiology department of Ghent University Hospital from February 2008 to June 2013. Height and weight were measured, and BSA was calculated according to the formulas of Du Bois and Du Bois5 (BSADB) and Haycock et al6 (BSAH). Blood pressure (BP) was measured before the ultrasound examination using a validated oscillometric BP

device (HEM-907; Omron Healthcare, Kyoto, Japan). Transthoracic echocardiography was performed by experienced adult and pediatric cardiologists using commercially available ultrasound equipment (Vivid 7; GE Vingmed Ultrasound AS, Horten, Norway) with adequate multifrequency transducers, ranging from 3.5 to 8 MHz for children and from 2 to 5 MHz for adults. Standard 2-dimensional parasternal long-axis, short-axis, and apical views of the proximal thoracic aorta, left ventricle, and left atrium were recorded. Color Doppler and continuous Doppler were used for the evaluation of valvular function. All proximal aortic diameters were assessed on 2-dimensional images in the parasternal long-axis view at end-diastole from leading edge to leading edge.7 The diameter of the AA was assessed at the level of the right pulmonary artery (Supplementary Figure 1). All aortic measurements were performed off-line by 3 experienced readers (JDB, LD, and LC). Interobserver variability is presented in Supplementary Table 1. This study was approved by the local ethics committee. Gender differences for body size parameters (height, weight, BSADB, BSAH, and body mass index [BMI]), systolic BP, diastolic BP, and proximal aortic dimensions were analyzed with the unpaired-sample Student’s t test for normally distributed continuous variables and with the MannWhitney U test for variables not normally distributed. Gender differences for aortic dimensions, adjusted for BSADB, were further analyzed in subgroups, with an age interval of 5 years before the age of 15 years and an age interval of 10 years after the age of 15 years, to investigate gender-related differences before and during puberty compared with after puberty. Correlation coefficients and univariate relations of morphologic parameters (weight, height, BSA, and BMI), age, BP, and SoV and AA diameters were assessed. For homogeneity of variance, the values of the aortic diameters, age, and morphologic parameters were transformed if necessary. Linear regression statistics were then applied. A spline regression model was computed with a spline knot set

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the aortic diameter measured at the level of the SoV or AA (log10[Ao]) (ULN ¼ 10[mean predicted log10(Ao) þ 1.96SEE]), and the z-score was defined as the number of SEEs greater than or less than the mean predicted log10(Ao) (z ¼ [measured lg10(Ao)  mean predicted log10(Ao)]/SEE). The cutoff for aortic dilatation was set at a z-score >1.96 SEEs or the ULN >1.96 SEEs of the mean predicted log10(Ao). Results are presented as mean  SD. Two-tailed p-values <0.05 were considered statistically significant. Results

Figure 2. Mean SoV diameter adjusted for BSADB in men (black bars) and women (white bars) per age interval of 5 years below the age of 15 years and per age interval of 10 years above the age of 15 years. NS ¼ not significant.

Figure 3. Mean AA diameters adjusted for BSADB in men (black bars) and women (white bars) per age interval of 5 years below the age of 15 years and per age interval of 10 years above the age of 15 years. NS ¼ not significant.

at the age of 15 years to allow a change in the regression slope due to the transition of a child to an adult. To correct for obesity (defined as BMI >95th percentile for subjects 18 years of age [using charts provided by the Centers for Disease Control and Prevention] and BMI >30 kg/m2 for subjects >18 years of age) within the cohort, obesity as a categorical variable was added to the model, together with an interaction term for obesity and BSA. Model selection was based on adjusted R2 values. Residual and regression diagnostic analyses were performed. The relation between standardized residuals of the linear regression models, body size parameters, and age was determined. After model selection, formulas and nomograms for ULNs and z-score calculations for the 2 aortic diameters were computed for male and female subjects. The ULN was defined as >1.96 SEEs greater than the mean predicted natural logarithm of

We included 849 Caucasian subjects (453 females, age range 1 to 85 years, mean 40.1  21.3, median 40.8 years). In all but 5 adult subjects, the AA diameter could be assessed. As shown in Supplementary Figures 2 and 3, all age decades and BSA categories are well represented. Body size parameters, BPs, age, and proximal thoracic aortic dimensions are listed in Table 1. The study population consisted of 12.8% patients with hypertension (109 of 849) (22.4% [108 of 483] in the subgroup aged 35 years). Most patients (95.4%) were adequately treated with antihypertensive medications. Plotting aortic diameters (SoV and AA) and body size parameters (height, weight, BSADB, and BSAH) against age indicated a faster increase in aortic dimensions before the age of 15 years, which was correlated with the increases in body size parameters before the age of 15 years (Figure 1). The change in diameter was similar for the SoV and AA as a function of age. From the age of 15 years on, BSADB-adjusted SoV diameters increased on average by 1.1  0.5 and 0.9  0.4 mm per decade for male and female subjects, respectively, and on average by 1.3  0.6 and 1.2  0.5 mm for BSADB-adjusted AA diameters (assessed with our multivariate models; see the following discussion). Proximal thoracic aortic diameters at all levels were significantly higher in male subjects in the entire group (p 0.001 for all diameters; Table 1). When the subgroup of pre- and peripuberty children (aged <15 years) was considered, we found only a small, borderline-significant gender difference at the level of the AA (18.9  2.9 and 17.8  3.2 mm for male and female subjects, respectively, p ¼ 0.048). Analysis of covariance, with BSADB adjustment, indicated that the gender differences remained statistically significant for those 15 years of age for the SoV and the AA (p <0.001 to 0.004; Figures 2 and 3). In contrast, below the age of 15 years, there were no significant gender differences after BSADB adjustment (Figures 2 and 3). Male subjects had on average, over all age decades 15 years, 2.4  0.3 and 1.4  0.3 mm larger BSADB- and ageadjusted SoV and AA diameters, respectively (assessed with our multivariate models; see the following discussion). Aortic dimensions at the level of the SoV and AA were most strongly correlated with age, BSA (both BSADB and BSAH), and weight (r ¼ 0.67 to 0.79, p <0.001 for all comparisons; Supplementary Table 2). Height yielded a strong correlation with aortic dimensions in children; in male and female subjects 15 years of age, height was only weakly correlated with aortic dimensions. Formulas for z-score and ULN calculation of the SoV and AA diameters were assessed using multiple regression for male and female subjects separately. The multivariate model with BSA and

Miscellaneous/Reference Values for the Proximal Aorta

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Figure 4. Nomograms displaying the ULN for SoV and AA diameters as a function of BSADB and age for both genders.

age (SoV, AA, and age were transformed to their natural logarithms) was selected on the basis of excellent adjusted R2 values (0.84 and 0.67 for the SoV and 0.82 and 0.74 for the AA, for male and female subjects, respectively; Supplementary Table 3). A model for BSADB and BSAH was computed. There were no significant linear relations between standardized residuals and BSADB, BSAH, weight, and age (r ¼ 0.047 to 0.051, p >0.28 for all comparisons). The distribution of the standardized residuals was not different between children and adults. Nomograms displaying the ULN for SoV and AA diameters as a function of BSADB are presented in Figure 4, and ULN values are presented in Supplementary Table 4. Equations providing the ULN and z-score as a function of BSA and age are listed in Table 2. There were no significant differences in the ULN for SoV and AA using BSADB compared with the ULN using BSAH for the total population (p ¼ 0.77 to 0.93) or for the subgroup of patients with BSAH 0.7 m2 (p ¼ 0.60 to 0.84). We applied different previously published formulas to the data set of patients included in this study to determine agreement with ULN values computed with the formulas we propose here. The differences between ULN values calculated with the various formulas are presented in Supplemental Table 5. Our values

correlate well and lie within the range of those calculated with the other available formulas. In particular, the small differences between the ULNs of SoV and AA dimensions calculated with our formula and those of Devereux1 and Gautier et al,8 respectively, are notable. Using the ULN and z-score formulas (with BSADB and BSAH) classified the same percentage of male and female normal subjects as having aortic dilatation (2% to 2.9% had zscores for the SoV >1.96, and 2.0% to 3.8% had z scores for the AA >1.96). Therefore, the aorta can be considered dilated when the z score is >1.96, with specificity of 96.2% to 98%. Below the age of 18 years, 4 male (3.8%) and 5 female (7.4%) subjects had BMIs >95th percentile; above the age of 18 years, 32 male (11%) and 40 female (10.4%) subjects had BMIs >30 kg/m2. Correction for obesity, however, did not influence adjusted R2 values. Applying a spline model with a spline knot set at the age of 15 years also did not improve our models. When considered in a univariate model, systolic BP and diastolic BP yield a strong relation with SoV and AA diameters (p <0.001 for all) (Supplementary Table 6). However, when added in the regression model with age and BSADB, this relation was no longer significant (p ¼ 0.28 to 1.00 for systolic BP and p ¼ 0.08 to 0.56 for diastolic BP).

ðLg10ðSoVÞ  ð1:108 þ 0:136 xLg10ðAgeÞ þ 0:099 x BSADB ÞÞ=0:0381 ðLg10ðSoVÞ  ð1:115 þ 0:137 xLg10ðAgeÞ þ 0:094 x BSAH ÞÞ=0:0388 ðLg10ðSoVÞ  ð1:100 þ 0:129 xLg10ðAgeÞ þ 0:091 x BSADB ÞÞ=0:0421 ðLg10ðSoVÞ  ð1:112 þ 0:132 xLg10ðAgeÞ þ 0:080 x BSAH ÞÞ=0:0427 ðLg10ðAAÞ  ð1:033 þ 0:188 x Lg10ðAgeÞ þ 0:070 x BSADB ÞÞ=0:0431 ðLg10ðAAÞ  ð1:038 þ 0:187 xLg10ðAgeÞ þ 0:068 x BSAH ÞÞ=0:0433 ðLg10ðAAÞ  ð1:001 þ 0:177 xLg10ðAgeÞ þ 0:086 x BSADB ÞÞ=0:0453 ðLg10ðAAÞ  ð1:006 þ 0:172 xLg10ðAgeÞ þ 0:087 x BSAH ÞÞ=0:0450 10 ð1:108 þ 0:136 x Lg10ðAgeÞ þ 0:099 x BSADB þ 1:96 x 0:0381Þ 10 ð1:115 þ 0:137 x Lg10ðAgeÞ þ 0:094 x BSAH þ 1:96 x 0:0388Þ 10 ð1:100 þ 0:129 x Lg10ðAgeÞ þ 0:091 x BSADB þ 1:96 x 0:0421Þ 10 ð1:112 þ 0:132 x Lg10ðAgeÞ þ 0:080 x BSAH þ 1:96 x 0:0427Þ 10 ð1:033 þ 0:188 x Lg10ðAgeÞ þ 0:070 x BSADB þ 1:96 x 0:0431Þ 10 ð1:038 þ 0:187 x Lg10ðAgeÞ þ 0:068 x BSAH þ 1:96 x 0:0433Þ 10 ð1:001 þ 0:177 x Lg10ðAgeÞ þ 0:086 x BSADB þ 1:96 x 0:0453Þ 10 ð1:006 þ 0:172 x Lg10ðAgeÞ þ 0:087 x BSAH þ 1:96 x 0:0450Þ Female

Male AA

Female

Male SoV

Discussion

AA ¼ ascending aorta; BSADB ¼ BSA calculated with the Dubois and Dubois formula; BSAH ¼ BSA calculated with the Haycock formula; SoV ¼ sinuses of Valsalva.

Z-score Equation Gender Aortic Level

ˇ

ˇ

ˇ

ˇ

ˇ

ˇ

ˇ

ˇ

Upper Limit of Normal Equation

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Table 2 Equations for upper limit of normal and z-score for proximal thoracic aorta dimensions using 2D echocardiography for males and females

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In this study, we propose nomograms and formulas for ULN and z-score calculation for 2 aortic locations (SoV and AA), on the basis of established guidelines7 and applicable for a wide age range. We demonstrate that age, body size, and gender are strong independent predictors of proximal aortic diameters. As expected, the increase in aortic dimensions is highest in children <15 years of age, which is directly related to the increase in body size parameters (Figures 1e3). From the age of 15 years on, the aortic growth rate is limited at all levels, with mean increases at the level of the SoV of 1.1 and 0.9 mm/decade for male and female subjects, respectively, and of 1.3 and 1.2 mm/decade at the AA level, when assessed with the multivariate models with BSADB. These findings are in accordance with previous ultrasound studies, which suggested a mean annual growth rate of 0.7 to 1 mm/year for the SoV and 0.7 to 2 mm/year for the AA in adults.1,9e11 Below the age of 15 years, we found no significant gender difference after BSADB correction. The latter finding is consistent with most pediatric studies with, among others, a large-scale study in 2,000 children.12e15 Only 1 pediatric study was able to demonstrate a small gender difference in BSA-adjusted SoV dimensions, but not for AA dimensions.8 In analogy with aortic dimensions, left ventricular mass and dimensions (with and without correction for BSA) do not differ between the genders in infancy and childhood.15,16 From the age of 15 years on, we observed a significant gender difference in SoV (2.4 mm) and AA (1.4 mm) diameters, after BSADB and age correction, suggesting a role for gender-specific hormones and/or genetic factors in aortic growth. Previous studies in adolescents and adults demonstrated a similar effect of male gender on SoV dimensions (2.4 to 2.7 mm).1,17 Only limited data regarding gender effects on AA diameters are available. A recently published large-scale computed tomographic study reported a gender difference for AA diameters of 1.04 mm.18 Studies so far have not shown a consistent independent association between BPs and aortic diameter. In general, hypertension appears to have a minor impact on proximal thoracic aortic dimensions when models are adjusted for age and BSA.19e21 When the absolute BPs are considered, the diastolic BP seems to be more strongly related to proximal thoracic aortic size in adults, especially to the AA diameter, than systolic BP.10,17e20,22 We did not observe a significant relation between BPs and aortic dimensions when included in the regression model with age and BSADB. At most, we observed a slight trend toward a higher impact of diastolic BP on AA diameters. The study population consisted of 12.8% patients with hypertension, of whom most were treated with antihypertensive medication. As previously demonstrated by Palmieri et al,19 treated hypertension seems not to be associated with aortic dilatation. To the best of our knowledge, data on the influence of treated hypertension on AA diameters are lacking. A total of 81 obese patients (BMI 30 to 35 kg/m2) were included in this study. A recent study suggested that obesity might be related to higher thoracic aortic dimensions over time.10 Obesity had no significant impact on proximal thoracic aortic dimensions when added to our multivariate models.

Miscellaneous/Reference Values for the Proximal Aorta

For the evaluation of aortic dimensions of an individual patient, both allometric methods for normalization to body size and regression models for diameter prediction, considering body size, age, and/or gender, have been published. We observed a significant interaction of aortic diameters with age and gender after BSA correction. Consequently, a prediction model considering body size, age, and gender was developed instead of normalizing to 1 explanatory parameter with an allometric scaling exponent. For the 2 approaches, BSA is the most commonly used parameter for body size estimation.4,8,12,15,23e27 BSA is subject to variability in individual subjects due to changes in body weight and is altered by obesity, which could lead to underestimation of cardiovascular measurements.28 Height has been advocated as an alternative for body size in allometric normalization of cardiovascular dimensions, as it remains constant throughout adulthood and is not influenced by obesity.28,29 Height has previously also been used in prediction models of SoV and AA dimensions.1,13 In our entire study population, height yielded good correlations with SoV and AA dimensions, which is due largely to a strong correlation during childhood, whereas in male and female subjects 15 years age, height was less strongly correlated with aortic dimensions compared with BSA. Therefore, height was not further considered in the regression model. Because the commonly used formula of Du Bois and Du Bois5 tends to underestimate BSA as values decrease to <0.7 m2,6,23 we constructed formulas based on the BSA calculated by the Haycock formula to overcome this problem. However, we did not observe significant differences in ULN predictions using BSAH versus BSADB. Our ULN values lie within the range of previously reported reference values (Supplementary Table 5). It would be of interest to perform a validation study of all available formulas in an independent cohort of patients with aortopathy. Some limitations should be noted. First, the crosssectional design of our study did not allow us to predict the influence on aortic diameters of time-dependent changes in parameters, such as body size parameters (e.g., weight gain). Second, this was a single-center study in which only Caucasian participants were included, possibly limiting the applicability of our data to other patient populations. Third, the study population comprised only 10% obese patients, especially in the age group >70 years, thus the prevalence of obesity was low. Likewise the number of elderly patients with high BSAs was limited. This may limit the applicability of the reference values to these specific subgroups. Fourth, our study population reflects the general population presenting at the cardiology department, which does not represent an entirely “normal” population, because in medical terms, “normal” indicates the absence of disease. However, factors associated with aortic dilatation, such as bicuspid aortic valve, connective tissue disorders, and significant valvular disease, were excluded in the studied population, and most patients with hypertension were treated with antihypertensive medications. Acknowledgments: We thank Roos Colman, of the biostatistics unit at Ghent University, for her assistance with the statistical analysis of the data.

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Disclosure The authors have no conflicts of interest to disclose. Supplementary Data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. amjcard.2014.06.024. 1. Devereux RB, De Simone G, Arnett DK, Best LG, Boerwinkle E, Howard BV, Kitzman D, Lee ET, Mosley TH Jr, Weder A, Roman MJ. Normal limits in relation to age, body size and gender of twodimensional echocardiographic aortic root dimensions in persons >/¼15 years of age. Am J Cardiol 2012;110:1189e1194. 2. Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE Jr, Eagle KA, Hermann LK, Isselbacher EM, Kazerooni EA, Kouchoukos NT, Lytle BW, Milewicz DM, Reich DL, Sen S, Shinn JA, Svensson LG, Williams DM. 2010 ACCF/AHA/AATS/ACR/ASA/ SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation 2010;121:e266ee369. 3. Muraru D, Maffessanti F, Kocabay G, Peluso D, Bianco LD, Piasentini E, Jose SP, Iliceto S, Badano LP. Ascending aorta diameters measured by echocardiography using both leading edge-to-leading edge and inner edge-to-inner edge conventions in healthy volunteers. Eur Heart J Cardiovasc Imaging 2014;15:415e422. 4. Biaggi P, Matthews F, Braun J, Rousson V, Kaufmann PA, Jenni R. Gender, age, and body surface area are the major determinants of ascending aorta dimensions in subjects with apparently normal echocardiograms. J Am Soc Echocardiogr 2009;22:720e725. 5. Du Bois D, Du Bois EF. A formula to estimate the approximate surface area if height and weight be known. 1916. Nutrition 1989;5:303e311. 6. Haycock GB, Schwartz GJ, Wisotsky DH. Geometric method for measuring body surface area: a height-weight formula validated in infants, children, and adults. J Pediatr 1978;93:62e66. 7. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440e1463. 8. Gautier M, Detaint D, Fermanian C, Aegerter P, Delorme G, Arnoult F, Milleron O, Raoux F, Stheneur C, Boileau C, Vahanian A, Jondeau G. Nomograms for aortic root diameters in children using two-dimensional echocardiography. Am J Cardiol 2010;105:888e894. 9. Patel HJ, Deeb GM. Ascending and arch aorta: pathology, natural history, and treatment. Circulation 2008;118:188e195. 10. Lam CS, Xanthakis V, Sullivan LM, Lieb W, Aragam J, Redfield MM, Mitchell GF, Benjamin EJ, Vasan RS. Aortic root remodeling over the adult life course: longitudinal data from the Framingham Heart Study. Circulation 2010;122:884e890. 11. Kalsch H, Lehmann N, Mohlenkamp S, Becker A, Moebus S, Schmermund A, Stang A, Mahabadi AA, Mann K, Jockel KH, Erbel R, Eggebrecht H. Body-surface adjusted aortic reference diameters for improved identification of patients with thoracic aortic aneurysms: results from the population-based Heinz Nixdorf Recall study. Int J Cardiol 2013;163:72e78. 12. Roman MJ, Devereux RB, Kramer-Fox R, O’Loughlin J. Twodimensional echocardiographic aortic root dimensions in normal children and adults. Am J Cardiol 1989;64:507e512. 13. Sheil ML, Jenkins O, Sholler GF. Echocardiographic assessment of aortic root dimensions in normal children based on measurement of a new ratio of aortic size independent of growth. Am J Cardiol 1995;75: 711e715.

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14. Daubeney PE, Blackstone EH, Weintraub RG, Slavik Z, Scanlon J, Webber SA. Relationship of the dimension of cardiac structures to body size: an echocardiographic study in normal infants and children. Cardiol Young 1999;9:402e410. 15. Kampmann C, Wiethoff CM, Wenzel A, Stolz G, Betancor M, Wippermann CF, Huth RG, Habermehl P, Knuf M, Emschermann T, Stopfkuchen H. Normal values of M mode echocardiographic measurements of more than 2000 healthy infants and children in central Europe. Heart 2000;83:667e672. 16. De Simone G, Devereux RB, Daniels SR, Meyer RA. Gender differences in left ventricular growth. Hypertension 1995;26:979e983. 17. Vasan RS, Larson MG, Levy D. Determinants of echocardiographic aortic root size. The Framingham Heart Study. Circulation 1995;91: 734e740. 18. Rogers IS, Massaro JM, Truong QA, Mahabadi AA, Kriegel MF, Fox CS, Thanassoulis G, Isselbacher EM, Hoffmann U, O’Donnell CJ. Distribution, determinants, and normal reference values of thoracic and abdominal aortic diameters by computed tomography (from the Framingham Heart Study). Am J Cardiol 2013;111:1510e1516. 19. Palmieri V, Bella JN, Arnett DK, Roman MJ, Oberman A, Kitzman DW, Hopkins PN, Paranicas M, Rao DC, Devereux RB. Aortic root dilatation at sinuses of Valsalva and aortic regurgitation in hypertensive and normotensive subjects: the Hypertension Genetic Epidemiology Network Study. Hypertension 2001;37:1229e1235. 20. Kim M, Roman MJ, Cavallini MC, Schwartz JE, Pickering TG, Devereux RB. Effect of hypertension on aortic root size and prevalence of aortic regurgitation. Hypertension 1996;28:47e52. 21. Agmon Y, Khandheria BK, Meissner I, Schwartz GL, Sicks JD, Fought AJ, O’Fallon WM, Wiebers DO, Tajik AJ. Is aortic dilatation an atherosclerosis-related process? Clinical, laboratory, and transesophageal echocardiographic correlates of thoracic aortic dimensions

22.

23. 24. 25.

26.

27. 28.

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