Reference Values for Mid-Ascending Aorta Diameters by Transthoracic Echocardiography in Adults

Accepted Manuscript

Reference Values for Mid Ascending Aorta Diameters by Transthoracic Echocardiography in Adults Chadi Ayoub MBBS , Gautam Kumar MBBS , Carin Y. Smith , Sandra C. Bryant MS , Diane M. Jech RCDS , Filip Ionescu MD , Ioana Petrescu MD , Fletcher A. Miller MD , Peter C. Spittell MD PII: DOI: Reference:

S0002-9149(18)31241-4 10.1016/j.amjcard.2018.06.006 AJC 23354

To appear in:

The American Journal of Cardiology

Received date: Revised date: Accepted date:

28 March 2018 26 May 2018 1 June 2018

Please cite this article as: Chadi Ayoub MBBS , Gautam Kumar MBBS , Carin Y. Smith , Sandra C. Bryant MS , Diane M. Jech RCDS , Filip Ionescu MD , Ioana Petrescu MD , Fletcher A. Miller MD , Peter C. Spittell MD , Reference Values for Mid Ascending Aorta Diameters by Transthoracic Echocardiography in Adults, The American Journal of Cardiology (2018), doi: 10.1016/j.amjcard.2018.06.006

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ACCEPTED MANUSCRIPT Reference Values for Mid Ascending Aorta Diameters by Transthoracic Echocardiography in Adults

Chadi Ayoub, MBBS a, b; Gautam Kumar, MBBS c; Carin Y. Smith d; Sandra C.

Fletcher A. Miller MD a; Peter C. Spittell, MD a

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Bryant, MS d; Diane M. Jech, RCDS a; Filip Ionescu, MD a; Ioana Petrescu, MD a;

a. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA b. Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA

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c. Division of Cardiology, Emory University / Atlanta VA Medical Center, Atlanta, GA d. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN

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Running Title: Mid ascending aorta size by echocardiography

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Corresponding Author:

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Peter C. Spittell, MD, FACC Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN,

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USA 55905

Telephone: 507-284-1644 Facsimile: 507-266-0103 E-mail: [email protected]

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Abstract We sought to characterize mid ascending aorta diameter reference values by age, sex and body surface area (BSA) in a large echocardiography laboratory practice-based cohort. All subjects with transthoracic echocardiograms with mid ascending aorta diameter measure from January 2004 through December 2009 were identified, and

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medical records were reviewed for medical history and anthropometric data. Those with aortic valve disease or replacement, congenital heart disease, any connective

tissue or inflammatory disease that may affect the aorta, or known aortic aneurysm (>55 mm) were excluded. Mid ascending aorta diameter was measured in a

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standardized manner using ‘leading edge to leading edge’ technique at end diastole. Of 27,839 eligible subjects, 16,620 did not have history of hypertension and were included in the analysis (56.3% female; mean age 52.0±15.8 years), mean mid

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ascending aorta diameter 31.7±4.1 mm. Females had smaller diameter than males (30.5±3.7 mm vs 33.3±4.0 mm; P<0.001). Subjects with history of hypertension

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(n=11,219; not included in the analysis) had larger mid ascending aorta diameter

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compared to normotensive subjects (33.9±3.8 mm vs 31.7±4.1 mm; P<0.001). Age had the greatest correlation with aortic size (r=0.55), followed by sex (r=0.35) and

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BSA (r=0.35). Nomograms for predicted mid ascending aorta diameter were generated at the 95th percentile using quantile regression for subjects without

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hypertension stratified by age, sex and BSA. In conclusion, mid ascending aorta diameter is predominantly associated with sex, age, and BSA. The nomograms established by this study may serve as useful reference values for echocardiographic screening and surveillance.

Keywords: Mid ascending aorta, size, echocardiography, age, sex

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INTRODUCTION Ascending aorta diameter has therapeutic and prognostic importance (1), and is routinely evaluated in patients undergoing transthoracic echocardiography (TTE). There are published reference ranges for the aortic root and proximal ascending aorta diameter using TTE (2-10). There are also studies defining normative ascending aorta

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diameters at all levels by computed tomography (CT) and magnetic resonance imaging (MRI), although there is variation between different modalities in the

techniques and timing of diameter measurement (11-16). However there are no

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published reference values specifically for mid ascending aorta diameter by TTE. Mid ascending aorta diameter has clinical importance in patients with aortopathies such as those associated with bicuspid aortic valve (BAV), hypertension, genetic syndromes including Marfan's and Loeys Dietz, and aortitis (17-19). Particularly in those with

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BAV or hypertension, aortic dilatation may occur above the proximal ascending aorta (Figure 1) (17, 20-22). In view of its clinical importance and absence of established

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echocardiographic data, we sought to characterize mid ascending aorta diameter

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METHODS

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reference values by age and sex in a large clinic based cohort.

The study was approved by the Mayo Foundation Institutional Review Board,

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and complies with the Declaration of Helsinki. We retrospectively evaluated all patients aged ≥20 years with TTEs performed at Mayo Clinic, Rochester, from January 2004 to December 2009. All subjects included had provided informed consent. Only the first echocardiogram for each patient was used. Mid ascending aorta diameter measurements were performed in a standardized manner throughout our laboratory. TTEs were performed in the left lateral decubitus

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position by trained sonographers, and reviewed by experienced cardiologists. Sonographers generally scanned one to two intercostal spaces above the standard parasternal long axis view to image the mid ascending level of the tubular ascending aorta above the proximal portion; in such views the aortic valve is generally no longer visualized (Figure 2). Diameters were measured perpendicular to the long axis of the

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aorta, in accordance with the American Society of Echocardiography (ASE)

guidelines, using leading-edge to leading-edge technique of the maximal distance between the anterior and posterior aortic walls at end diastole (20).

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In order to perform an internal validation to test the reliability of mid

ascending aorta measures with independent remeasurements by intra-class correlation analysis, a sample size of 300 subjects was determined as necessary to test a null hypothesis of ρ=0.6 vs 0.5. Thus 300 subjects were randomly selected and had their

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echocardiogram images retrieved. The mid ascending aorta diameter was independently remeasured by an experienced senior echocardiographer, and image

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quality was also assessed. The duplicate mid ascending aorta diameter values were

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compared to test the reliability of measurements included in this study. Clinical information was obtained from the patients’ medical records prior to

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their index echocardiographic examination, including history of hypertension and other cardiovascular risk factors, as well as conditions listed in the exclusion criteria

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below. These were identified using International Classification of Disease (ICD) 9 diagnosis codes. History of smoking was defined as current or former smokers based on patient provided information or as patients with ICD-9 diagnosis codes for tobacco abuse. Demographic data including age, sex, height, weight, blood pressure and heart rate measurements were obtained at the index echocardiographic examination. BSA was calculated according to the Du Bois formula.

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Exclusion criteria based on TTE data included BSA <1.35 and ≥2.35 m2, body mass index (BMI) <18 and ≥45 kg/m2, aortic stenosis of any degree, aortic regurgitation greater than mild in severity, BAV, aortic valve replacement, and mid ascending aorta diameter ≥55 mm. All subjects with history in their electronic medical records of the following conditions, which may potentially be associated with

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aortic dilatation, were also excluded: Ehlers Danlos, Marfan, and Loeys-Dietz

syndromes, connective tissue disease, giant cell arteritis, aortitis, Behçet’s disease, Takayasu or Kawasaki disease, congenital heart disease, prior aortic aneurysm or

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dissection, heart transplant, syphilitic heart disease, coronary artery disease, stroke, or hypertension (Supplemental Data, Figure S1).

Comparisons of baseline characteristics by sex were performed using t–tests for continuous variables and chi-square tests for categorical variables. Intraclass

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correlation coefficient (ICC) analysis was used to test the reliability of repeated measurements for mid ascending aorta diameter. Correlation between mid ascending

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aorta diameter and anthropometric variables was evaluated by utilizing Pearson

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correlation coefficients.

Univariate quantile regression models were fit at the 95th percentile to assess

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associations between baseline characteristics and mid ascending aorta diameter. Analysis was performed for the entire cohort, then stratified by sex. Sex-specific

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relationships of mid ascending aorta diameter were evaluated using quantile regression models at the 95th percentile, using backward selection to eliminate nonsignificant covariates and achieve the most parsimonious model for estimating reference limits. As height, BMI and BSA are associated with one another, each was assessed separately with other covariates. Once the most parsimonious model was achieved from baseline characteristics, several additional multivariable models were

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fit to explore potential interactions or non-linear associations. The best fitting multivariable model with the least variables was selected within each sex after comparing the goodness of fit using R1 and Akaike information criterion (AIC) values. The model R1 is a measure of goodness of fit in the quantile being estimated, is similar to R2, and frequently used with quantile regression models (23). All

NC). Statistical significance was defined as P <0.05.

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RESULTS

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statistical analysis was performed using SAS version 9.4 (SAS Institute Inc, Cary,

After applying inclusion and exclusion criteria to consecutive adult TTEs, 16,620 subjects (56.3% female; mean age 52.0 ± 15.8 years) were eligible for analysis. Clinical and echocardiographic characteristics are shown in Table 1. Mean

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mid ascending aorta diameter was 31.7 ± 4.1 mm. Females had smaller mean diameter than males (30.5±3.7 mm vs 33.3±4.0 mm; P<0.001). In subjects excluded from the

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reference value analysis due to history of hypertension (n=11,219), mean diameter

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was larger than in those without hypertension (33.9±3.8 mm vs 31.7±4.1, P<0.001). To test the reliability of mid ascending aorta diameter measures acquired from

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our laboratory, 300 patients were randomly selected for duplicate measurement. The mean mid ascending aorta diameter for the original measurements was 33.3 mm, and

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mean diameter on repeat measurement was 33.3 mm, P=0.94 on matched pair t-test. The range in difference of measures between original measurement and its duplicate was 0-3 mm. ICC coefficient was 0.97 (95% CI: 0.968, 0.980) suggesting excellent reliability of original measures and consistency of raters. Review of the same sample for image quality rated 64% (n=191) as of ‘good quality’, 36% (n=109) as ‘adequate but imperfect quality’ and none as of ‘poor quality’.

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Age had the greatest correlation with aortic size [r=0.55], followed by sex [r=0.35], BSA [r=0.35], weight [r=0.32] and height [r=0.26]. To simplify modeling, all subsequent analyses were performed separately for males and females. Sexspecific univariate models demonstrated significant associations at the 95th percentile for several characteristics with increasing mid ascending aorta diameter size; age was

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the most important, followed by increase in blood pressure, BSA, BMI and weight, but not height (Table 2).

Multivariable modeling of the 95th percentile of mid ascending aorta diameter

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was performed, with backward selection of all characteristics. Height, BMI and BSA were assessed separately with the remaining characteristics, with BSA consistently providing the best fitting models for each sex. The resulting models were created for the different age groups (per decade age change) and plots generated (Table 3, Figures

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3 and 4). Scatter plots of the observed values with the 95th percentile for mid ascending aorta diameter for each sex by decade of age are shown Supplemental

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Figures S2 and S3; due to the paucity of data for ages 90-99 in this cohort, the 95th

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percentile for this group was not included in the reference plots in Figures 3 and 4.

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DISCUSSION

This study characterizes upper reference limits of mid ascending aorta

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diameter systematically measured by 2-dimensional TTE in a very large practicebased cohort, and provides nomograms which can be used as reference values by age, sex and BSA (Figures 3 and 4) in subjects without hypertension. These reference values may assist in the diagnosis and follow-up of patients at risk for aortopathy affecting the tubular portion of the ascending aorta. Our study confirms the

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correlation of increasing aorta size with age, sex, BSA and hypertension which have been demonstrated in previous work (2-6, 8, 10). Ascending aorta diameter is a routinely measured parameter on TTE that has therapeutic and prognostic importance. Patients with BAV are at risk of aneurysm formation at the mid ascending aorta level in particular (17, 21, 22). Hypertension

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appears to be associated with enlargement of more distal aortic segments, with

minimal impact to the aortic root (20). Aortic dilatation in patients with aortitis and genetic aortopathies, including Marfan and Loeys Dietz, may also occur above the

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proximal ascending aorta level.

Accurately defining normal size is necessary clinically, as aortopathy and increasing aortic size are associated with risk of dissection, rupture and death (24, 25). In addition, aortic size is used to guide the decision for surgical intervention (1, 26).

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Whilst there are published reference ranges for the sinus of Valsalva, sinotubular junction and proximal ascending aorta diameter using TTE, there are no published

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standardized measurements specifically for mid ascending aorta diameter, which our

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study has sought to establish.

Current guidelines define the ‘normal’ range (values within the 95%

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confidence interval) on two-dimensional TTE for diameter at different levels within the aortic root and proximal ascending aorta (8, 20, 26). Recent studies define

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reference ranges for aortic root and proximal ascending aorta in cohorts ranging from 700 to 1200 patients using leading edge to leading edge technique at end diastole (2, 4, 7, 9, 27). Mirea et al and Vizzardi et al in well-designed studies of 500 and 2029 subjects respectively provide reference measures of the aortic root and ‘largest aortic ascending aorta diameter’ using inner edge to inner edge technique (5, 10). Our study is the first to systematically measure mid ascending aorta diameter in a standardized

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manner at end diastole by the leading-edge convention in accordance with current TTE guidelines (Figure 2) (20, 28). In the current clinical setting of multimodality imaging, normative ascending aorta diameters using CT and MRI have been defined. However there is controversy about timing and technique, and CT and MRI differ from TTE in that they measure

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aorta diameter by ‘inner edge to inner edge’ technique, and some studies make measurements at end-systole (11-16, 29). Good correlation in aortic size

measurements between echocardiography and CT have been reported, with measures

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by TTE in the aortic root and ascending aorta being slightly smaller than those by CT (30). Although multiplanar reconstructions by CT and MRI afford better visualization of the aorta, in clinical practice TTE is the first line imaging technique, highlighting the need for accurate and reproducible reference values.

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The ascending aorta and arch are retrosternal structures that have a complex anatomic course traversing from right to left and anterior to posterior. However the

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tubular mid ascending aorta may not be adequately visualized from standard

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parasternal views, and the transducer may need to be moved up one or two intercostal spaces and tilted closer to the sternum to improve visualization (20). Although TTE

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allows accurate and reproducible measurements of aortic root and proximal ascending aorta diameters (20, 28), if oblique cuts are acquired of the aortic root, it is possible to

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get small variations in measurements even within the same study. As such, the mid ascending aorta may represent a more reliable and reproducible level for ascending aorta measurements, although there is no data at present to evaluate this. Although in practice the largest diameter measured from the best visualized portion of the mid ascending aorta is recorded, when making serial measurements it is also important to measure at a comparable level to the preceding study to assist in surveillance.

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This study confirms feasibility of standardized measurement of mid ascending aorta diameter from a large practice. In a sensitivity analysis of 300 randomly selected subjects for duplicate measurement, excellent correlation was obtained with the clinical measures. Review of image quality rated images as either of good or adequate quality, and there were no poor quality images in the randomly selected sample; as it

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is the policy of our laboratory not to report measures where image quality is poor, it was thus anticipated that the measures included in this study would be of at least

adequate quality. Thus a limitation of this study is that the number of examinations

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with poor image quality at the mid ascending aorta could not be assessed.

Other limitations include possible referral bias as the study was conducted in a tertiary referral centre with patients undergoing TTE for various clinical indications. However, every effort was made to exclude known disease that may be associated

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with ascending aorta dimension, and in general reference values often include patients with comorbidities unrelated to the question at hand. Future work may help determine

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event related significant cut-offs for this level of the aorta as measured by TTE.

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The nomograms established by this study may serve as a useful reference for clinical management and follow up. Mid ascending aorta diameter is predominantly

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correlated with sex, age, BSA and hypertension.

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Funding and Disclosures: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors do not have any conflicts of interest to declare. Acknowledgements: We thank Bruce Daniels RCDS for his meticulous and tireless work in procuring and checking the data, and Mr. Prabin Thapa, Dr. Kent Bailey, and Dr. Phillip Schulte for their involvement with the preliminary statistics work.

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FIGURE LEGEND

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Figure 1. Demonstrated is dilatation predominantly affecting the mid ascending aorta demonstrated, which may occur particularly in aortopathies such as those associated with BAV, hypertension and familial aortopathy syndromes.

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Figure 2. A. TTE from high parasternal view, demonstrating the mid ascending level of the ascending aorta. This is generally obtained by scanning one to two intercostal

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spaces above the standard parasternal long axis view, and the aortic valve is usually not visualized at this level. B. Demonstrates zoomed in view of the aortic root from

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the parasternal long axis view, demonstrating measurements (left to right) at the level

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of the sinus of Valsalva, sinotubular junction (STJ) and proximal ascending aorta respectively (at end diastole, using leading edge to leading edge technique). C and D.

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Images from the same patient with giant cell arteritis and dilatation of the ascending aorta; Panel C demonstrates measurements at the STJ and proximal ascending aorta from standard parasternal long axis view, and panel D shows the mid ascending aorta diameter measure obtained 2 intercostal spaces higher, where the dilatation is greatest.

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Figure 3. Nomograms with predicted 95th percentiles for mid ascending aorta

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diameter by age (per decade) for women.

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Figure 4. Nomograms with predicted 95th percentiles for mid ascending aorta

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diameter by age (per decade) for men.

Table 1. Baseline characteristics at the time of echocardiogram. Characteristics Age (years) Non-white race or Hispanic ethnicity Height (m) Weight (kg) 2 Body mass index (kg/m ) 2 Body surface area (m )

Women (n=9364) 51.0 ± 15.9

Men (n=7256) 53.3 ± 15.6

Total (n=16,620) 52.0 ± 15.8

581 (6.2%)

459 (6.3%)

1040 (6.3%)

0.75

1.6 ± 0.1 73.0 ± 15.9 27.1 ± 5.7 1.8 ± 0.2

1.8 ± 0.1 86.1 ± 13.1 27.1 ± 4.0 2.0 ± 0.2

1.7 ± 0.1 78.7 ± 16.1 27.1 ± 5.1 1.9 ± 0.2

<0.001 <0.001 0.39 <0.001

P-value <0.001

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Hyperlipidemia Mid ascending aorta diameter (mm)

115 ± 16

118 ± 15

117 ± 15

<0.001

69 ± 10

71 ± 10

70 ± 10

<0.001

74 ± 14 3757 (40.1%) 509 (5.4%)

70 ± 15 3781 (52.1%) 516 (7.1%)

72 ± 14 7538 (45.4%) 1025 (6.2%)

<0.001 <0.001 <0.001

1780 (19.0%)

1672 (23.0%)

3452 (20.8%)

<0.001

30.5 ± 3.7

33.3 ± 4.0

31.7 ± 4.1

<0.001

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Systolic blood pressure a (mmHg) Diastolic blood pressure b (mmHg) c Heart rate (bpm) d Smokers Diabetes mellitus

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Continuous variables are presented as mean ± standard deviation and compared by sex using t-tests, categorical variables are presented as n (%) and compared by sex using chi-square tests. Abbreviations: bpm, beats per minute; kg, kilograms; m, metres; mmHg, millimetres of mercury. 322 (195 females, 127 males) are missing systolic blood pressure. 308 (191 females, 117 males) are missing diastolic blood pressure. 671 (376 females, 295 males) are missing heart rate. Includes current or previous smokers

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anthropometric data. Characteristics

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Table 2. Univariate associations of mid ascending aorta diameter with

Pearson Correlation

Model 1 R

Rate of Change (95% CI)

P-value

9364

0.55

0.132

1.454 (1.346, 1.561)

<0.001

9364

-0.07

0.003

-1.000 (-1.132, -0.868)

<0.001

9364 9364 9364 9364

0.01 0.22 0.22 0.20

0.000 0.009 0.009 0.007

0.000 (-0.166, 0.166) 0.172 (0.119, 0.226) 0.098 (0.066, 0.131) 0.262 (0.180, 0.343)

1.00 <0.001 <0.001 <0.001

9169

0.25

0.036

0.500 (0.378, 0.622)

<0.001

9173

0.17

0.024

0.192 (0.112, 0.272)

<0.001

8988 9364 9364 9364

-0.01 0.05 0.06 0.12

0.038 0.000 0.000 0.001

0.000 (-0.064, 0.064) 0.000 (-0.135, 0.135) 0.000 (-0.045, 0.045) 1.000 (0.112, 1.888)

1.00 1.00 1.00 0.03

7256

0.58

0.168

1.744 (1.608, 1.880)

<0.001

7256

-0.11

0.002

-1.000 (-1.982, -0.018)

0.05

7256 7256

0.03 0.20

0.000 0.009

0.000 (-0.033, 0.033) 0.248 (0.159, 0.337)

1.00 <0.001

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Women Age (per 10 years) Non-white race or Hispanic ethnicity Height (per 10 cm) Weight (per 5 kg) 2 Body mass index (per 5 kg/m ) 2 Body surface area (per 0.1 m ) Systolic blood pressure (per 10 mmHg) Diastolic blood pressure (per 5 mmHg) Heart rate (per 10 bpm) Smokers Diabetes mellitus Hyperlipidemia Men Age (per 10 years) Non-white race or Hispanic ethnicity Height (per 10 cm) Weight (per 5 kg)

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Body mass index (per 5 kg/m ) 2 Body surface area (per 0.1 m ) Systolic blood pressure (per 10 mmHg) Diastolic blood pressure (per 5 mmHg) Heart rate (per 10 bpm) Smokers Diabetes mellitus Hyperlipidemia

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7256 7256

0.19 0.17

0.010 0.005

0.185 (0.121, 0.248) 0.351 (0.196, 0.505)

<0.001 <0.001

7129

0.13

0.020

0.278 (0.046, 0.510)

0.02

7139

0.08

0.016

0.000 (-0.000, 0.000)

0.95

6961 7256 7256 7256

0.03 0.11 0.07 0.06

0.043 0.000 0.000 0.000

0.000 (-0.034, 0.034) 0.000 (-0.545, 0.545) 0.000 (-1.000, 1.000) 0.000 (-0.404, 0.404)

1.00 1.00 1.00 1.00

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‘Model R1’ shows goodness of fit for each quantile regression model. ‘Rate of Change’ refers to per millimeter change in mid ascending aorta diameter for each variable from quantile regression model fit at the 95th percentile. Abbreviations: bpm, beats per minute; kg, kilograms; m, meters; mmHg, millimeters of mercury.

Table 3. Multivariable regression models for association of mid ascending aorta diameter with age and body surface area at the 95th percentile.

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Model R 0.172

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N 9364

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Characteristics Women Age (per 10 years) 2 Age (per 10 years) Body surface area 2 (per 0.1 m ) Men Age (per 10 years) Body surface area 2 (per 0.1 m )

1

Rate of Change (95% CI)

P-value

2.322 (1.848, 2.797) -0.079 (-0.126, -0.031)

<0.001 0.001

0.517 (0.442, 0.593)

<0.001

1.747 (1.642, 1.851)

<0.001

0.516 (0.406, 0.627)

<0.001

0.190

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‘Model R1’ shows goodness of fit for each quantile regression model. ‘Rate of change’ refers to per millimeter change in mid ascending aorta diameter for each variable from quantile regression model fit at the 95th percentile. Abbreviations: bpm, beats per minute; kg, kilograms; m, meters; mmHg, millimeters of mercury.