PLoS ONE plos plosone PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0280530 PONE-D-22-24629 Research Article Medicine and health sciencesDiagnostic medicineDiagnostic radiologyUltrasound imagingEchocardiography Research and analysis methodsImaging techniquesDiagnostic radiologyUltrasound imagingEchocardiography Medicine and health sciencesRadiology and imagingDiagnostic radiologyUltrasound imagingEchocardiography Research and analysis methodsImaging techniquesNeuroimagingComputed axial tomography Biology and life sciencesNeuroscienceNeuroimagingComputed axial tomography Medicine and health sciencesDiagnostic medicineDiagnostic radiologyTomographyComputed axial tomography Research and analysis methodsImaging techniquesDiagnostic radiologyTomographyComputed axial tomography Medicine and health sciencesRadiology and imagingDiagnostic radiologyTomographyComputed axial tomography Biology and life sciencesAnatomyCardiovascular anatomyHeartAortic valve Medicine and health sciencesAnatomyCardiovascular anatomyHeartAortic valve Medicine and health sciencesSurgical and invasive medical procedures Medicine and health sciencesClinical medicineSigns and symptomsStenosis Medicine and health sciencesSurgical and invasive medical proceduresCardiovascular proceduresCoronary artery bypass grafting Biology and life sciencesAnatomyCardiovascular anatomyBlood vesselsAorta Medicine and health sciencesAnatomyCardiovascular anatomyBlood vesselsAorta Research and analysis methodsMathematical and statistical techniquesStatistical methodsRegression analysis Physical sciencesMathematicsStatisticsStatistical methodsRegression analysis Differences in aortic valve area measured on cardiac CT and echocardiography in patients with aortic stenosis Aortic valve area on cardiac CT and Echocardiography https://orcid.org/0000-0003-0486-4626 Choe Jooae Data curation Formal analysis Investigation Methodology Software Visualization Writing – original draft Writing – review & editing 1 https://orcid.org/0000-0001-5640-3835 Koo Hyun Jung Conceptualization Data curation Formal analysis Investigation Methodology Project administration Resources Software Validation Visualization Writing – original draft Writing – review & editing 1 * https://orcid.org/0000-0001-7327-6102 Choi Se Jin Formal analysis Investigation Writing – original draft 1 Lee Seung-Ah Data curation Writing – review & editing 2 Kim Dae-Hee Writing – review & editing 2 Song Jong-Min Writing – review & editing 2 Kang Duk-Hyun Writing – review & editing 2 Song Jae-Kwan Writing – review & editing 2 Kang Joon-Won Writing – review & editing 1 Yang Dong Hyun Conceptualization Writing – review & editing 1 Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea Division of Cardiology, Cardiac Imaging Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea Wang Tom Kai Ming Editor Cleveland Clinic, UNITED STATES

The authors have declared that no competing interests exist.

 * E-mail: elfin19@gmail.com 20 1 2023 2023 18 1 e0280530 3 9 2022 29 12 2022 2023 Choe et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background

A certain proportion of patients with severe aortic stenosis (AS) present with discordant grading between different diagnostic modalities, which raises uncertainty about the true severity of AS. The aim of this study was to compare the aortic valve area (AVA) measured on CT and echocardiography and demonstrate the factors affecting AVA discrepancies.

 Methods

Between June 2011 and March 2016, 535 consecutive patients (66.83±8.80 years, 297 men) with AS who underwent pre-operative cardiac CT and echocardiography for aortic valve replacement were retrospectively included. AVA was obtained by AVA on echocardiography (AVAecho) and CT (AVACT) using a measurement of the left ventricular outflow tract on each modality and correlations between those measures were evaluated. Logistic regression analysis was performed to identify factors affecting the discordance for grading severe AS.

 Results

The AVACT and AVAecho showed a high correlation (r: 0.79, P <0.001) but AVACT was larger than the AVAecho (difference 0.26 cm2, P <0.001). By using the cut-off values of AVACT (<1.2 cm2) and AVAecho (<1.0 cm2) for diagnosing severe AS, the BSA (odds ratio [OR]: 68.03, 95% confidence interval [CI]: 5.45–849.99; P = 0.001), AVAecho (OR: 1.19, 95%CI: 1.14–1.24; P <0.001), tricuspid valve morphology (OR: 2.83, 95%CI: 1.23–6.50; P = 0.01), and normalized annulus area (OR: 1.02; 95%CI:1.02–1.03; P <0.001) were significant factors associated with the discordance between the AVAecho and AVACT.

 Conclusion

Patients with larger BSA, AVAecho, and annulus, and tricuspid valve morphology were associated with the AVA discordance between the echocardiography and CT. Complementary use of CT with echocardiography for grading severe AS could be helpful in such conditions.

 Korea government 2022R1A5A1022977 This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No.2022R1A5A1022977). Data Availability The datasets generated during and/or analysed during the current study are not publicly available due to the policy of Institutional Ethics Committee but are available from the corresponding author (radkoo@amc.seoul.kr) on reasonable request, or from the following point of contact: - Name: Hong Min Oh - Affiliation: Asan Medical Center, Medical Imaging and Intelligent Reality Lab, Data management part - E-mail: ohm0124@gmail.com. 1. Introduction

Aortic stenosis (AS) is the most common valvular disease, and severe or symptomatic AS needs surgical or transcatheter aortic valve replacement (TAVR) [1, 2]. Unlike surgical aortic valve replacement (AVR), intraprocedural valve size evaluation is not possible in TAVR, and measuring the appropriate aortic annulus size is critical for the patient’s outcome. To avoid complications in TAVR, such as aortic annulus rupture, paravalvular leak, and coronary artery obstruction, careful evaluation of the ventriculo-aortic transition is crucial. Moreover, in patients suspected of having significant AS, assessing the degree of AS is important in making decisions on stratified treatments and the timing for surgical intervention since the risk of waiting increases in correlation to the degree of AS [3]. A recent study demonstrated that surgical intervention could improve survival even among asymptomatic patients with severe AS [4]. The decision to perform surgery in an asymptomatic patient requires careful weighting of the risks of early AVR against those of observation.

The evaluation of the aortic apparatus and severity of AS is usually assessed by a transthoracic echocardiography (TTE) [5]. In a Doppler echocardiography, the single diameter of the aortic annulus (left ventricular outflow tract [LVOT] cross-sectional area) was used to calculate the aortic valve area (AVA). However, the aortic apparatus is a complex structure, and fibrocalcific changes of the aortic valve (AV) make evaluating the AV and annulus size on a 2D echocardiography alone difficult [6]. Due to the need for accurate preprocedural measurement of the aortic annular size, 3D-echocardiography and multidetector cardiac computed tomography (CT) have been widely used as potential alternatives to improve annulus measurements. On cardiac CT scans, we can obtain an AVA not only by the continuity equation (AVACT) but also by the planimetry method drawing the inner margin of the aortic cusps (AVAplani). Several studies showed a good correlation between the CT-derived AVA and AVAecho calculated with the continuity equation using TTE measurements [7–10].

However, the AVA obtained by CT did not improve the correlation with the transaortic pressure gradient and yielded a greater AVA value than the AVAecho; thus, a larger AVACT cut-off value was recommended for diagnosing severe AS [11–13]. Previous studies suggested several explanations for the differences between the AVACT and AVAecho. One study suggested that a smaller AVAecho is related to the underestimation of the LVOT area with a single anteroposterior diameter of the LVOT, where the LVOT is an elliptical rather than round in aortic valvular disease [14]. Another study’s proposed explanation was that the difference might show the difference in the maximum anatomical AVA and functional vena contracta, the narrowest portion of the stenotic flow that reflects a pressure gradient [15]. A third explanation is that on a CT scan, the AVA is measured at the systolic phase, whereas the average systolic phase parameters were used in the continuity equation [16].

It is unknown which modality, echocardiography or CT, is more accurately in grading AS, but the downgrade in diagnosis from severe AS by echocardiography to moderate AS by CT may change the timing of surgical treatments and could even reduce the number of patients that require AVR or TAVR. In addition, the effect of fibrocalcific changes of the AV and other echocardiographic characteristics in the discordance of classifying AS based on the AVAecho and AVACT has not been sufficiently evaluated. Thus, the aims of our study are to confirm the correlation between the AVAecho and CT-derived AVA and to evaluate the factors resulting in the discordance between AVAecho and AVACT when classifying severe AS.

 2. Methods 2.1. Study patients

This retrospective study was approved by the Institutional review board (IRB) of our hospital (approval number: 2018–0233) and informed consent was waived. Between June 2011 and March 2016, 781 patients underwent surgical AVR. Exclusion criteria included patients with concomitant significant aortic regurgitation (qualitatively defined as moderate or higher degree based on echocardiographic findings; n = 177), quadricuspid AV (n = 1), or had no available preoperative cardiac CT scan (n = 47) or multiphase CT scan data (n = 21). Finally, 535 patients were included in the study. Clinical characteristics such as age, body surface area (BSA), hypertension, atrial fibrillation, heart failure, B-type natriuretic peptide (BNP), and outcomes, echocardiography parameters, and preoperative cardiac CT data were collected.

 2.2. Echocardiography

All patients underwent a transthoracic echocardiography preoperatively using commercially available ultrasound machines with 3–5 MHz real-time transducers (iE33, EPIC; Philips Medical Systems, Andover, MA; Vivid 7, E9, General Electric Healthcare, Waukesha, WI, USA). Expert cardiologists obtained conventional two-dimensional and Doppler images according to the American Society of Echocardiography recommendations [17]. Color Doppler or three-dimensional images was obtained when clinically necessary. AS severity was semi-quantitatively measured and graded using four grades. Left ventricular ejection fraction (LVEF), AV velocity time integral (VTI), LVOT VTI, AVA, and volumetric parameters, including end-systolic volume and end-diastolic volume, were calculated. The maximal and mean pressure gradient (PG) across the AV were estimated using a modified Bernoulli equation, and the AVA was calculated from the continuity equation with VTI (AVAecho; Fig 1). Classic low-flow/low-gradient (LF/LG) severe AS was defined as AVAecho less than 1 cm2 but with a low gradient (<40 mmHg). Low-gradient severe AS with preserved LVEF was defined as paradoxical LF/LG AS.

10.1371/journal.pone.0280530.g001 An example of aortic valve area (AVA) measurement using echocardiography or CT in a 74-year-old male who diagnosed as severe stenosis of fused bicuspid aortic valve.

AVA, aortic valve area; LVOT, left ventricular outflow tract; VTI, velocity time integral.

 2.3. Cardiac CT protocol and image analysis

A cardiac CT scan was performed preoperative using a second-generation dual-source CT scanner (Somatom Definition Flash; Siemens Medical Solutions, Forchheim, Germany). Unless contraindicated, 2.5 mg oral bisoprolol (Concor; Merck, Darmstadt, Germany) was administered to patients with heart rates greater than 75 beats/min one hour prior to the CT scan for coronary artery evaluation. A bolus of 60–80 mL of nonionic, iodinated contrast material (Iomeron; Bracco Imaging SpA, Milan, Italy) was injected using a power injector (Stellant D; Medrad, Indianola, PA, USA) at 3.0 mL/s, followed by 40 mL of a 30:70 mixture of contrast and saline using the bolus tracking method (ascending aorta; trigger threshold level 100 HU; scan delay, 8 s). In our center, for baseline work up in patients with aortic valvular disease, multiphase cardiac CT is routinely performed prior to making the decision between surgery or TAVR as multiphase cardiac CT can provide information regarding the exact motion of aortic leaflets as well as morphological information regarding the aortic root and CT findings are also important in determining those treatment options. Retrospective electrocardiogram-gated scanning was performed with a 20% tube current modulation (dose pulsing windows, 20%–70% of the R-R interval) to minimize the radiation dose. In patients with arrhythmia, 0%–90% of the R-R interval was used. The tube voltage and the tube current-time product were adjusted for body size. The scan parameters were as follows: tube voltage, 80–120 kV; tube current, 160–360 mAs; pitch, 0.17–0.38; detector collimation, 64 × 0.6 mm and gantry rotation time, 280 ms. For preoperative evaluation of the aorta, most patients underwent CT of the thorax and abdomen and cardiac CT. Therefore, the dose length product (DLP) and the effective dose (ED) values were slightly higher compared to those used for routine cardiac CT scans. In all patients, the mean ± standard deviation DLP for the cardiac CT scans was 1187.2 ± 547.7 mGy·cm, and the mean ED was 16.6 ± 7.7 mSv.

Post-processing was conducted using an external workstation (AquariusNet; TeraRecon, Foster City, CA, USA) using multiphase CT data sets reconstructed by a 10% R-R interval. CT characteristics such as AV morphology (tricuspid, bicuspid with raphe, bicuspid without raphe), AVACT, AVA plani, aortic annulus diameter, circularity (minimum diameter/maximum diameter), perimeter, and area, and diameters of the sinus of Valsalva, sinotubular junction, and ascending aorta tubular portion were measured by two radiologists in consensus. AVACT was calculated by using the LVOT area measured on CT (3D circular LVOT area approximated by πr2 with average diameter used for r) in the continuity equation with VTI at LVOT and transaortic flow on echocardiography (a hybrid of measures from both CT and echocardiography; AVACT = LVOTCT × VTILVOT/VTIAo; Fig 1). For AVAplani, the following steps were performed: 1) selecting the end-systolic phase showing maximal aortic opening; 2) generating an AV in the en-face view from the sinuotubular junction to LVOT level using 1 mm thick images and 3) measuring the largest AVA on an image with 5–10 mm slab thickness, generated from a multiplanar reformation to optimally visualize the lines of the AV tips. To evaluate the reliability of the CT measurements, a third experienced radiologist measured the CT parameters in 100 randomly selected cases, and an interobserver agreement was determined. Observers were blinded to the clinical data, including echocardiography findings and operation records.

 2.4. Statistical analysis

Continuous variables were expressed as mean ± standard deviation or as median and interquartile range (IQR). Categorical variables are presented as numbers and percentages. Measurement variability was assessed by using intraclass correlation (ICC) for agreement between the image readers. The AVA measured on the echocardiography (AVAecho) and CT (AVACT) were compared using a paired Student t- test. Agreement between the two modalities were assessed using ICC and the mean absolute difference was plotted using the Bland-Altman analysis to assess measurement differences in the AVAecho and AVACT. Correlation between the AVAecho and AVACT was analyzed using the Pearson’s correlation coefficient (r).

Patients were classified into either the concordant group (AVAecho < 1.0 cm2 and AVACT < 1.2 cm2) or the discordant group (AVAecho < 1.0 cm2 and AVACT ≥ 1.2 cm2) for grading severe AS [11–13]. The two groups were compared using the Student’s t-test and Chi-square test or Fisher’s exact test. Logistic regression analysis was performed to identify clinical and imaging parameters associated with the discordance group. Areas under the receiver operating characteristic curve (AUCs) were generated for each significant variable from a multivariable analysis. The cut-off values of the various parameters were identified and tested to maximize the Youden index (sensitivity + specificity − 1). All statistical tests were two-sided, and a P value less than 0.05 was used as a threshold for identifying a significant difference. Statistical analysis was performed using commercial software (SPSS, version 23; SPSS, Chicago, IL, USA).

 3. Results 3.1. Patient characteristics

A total of 535 patients (mean age, 66.83 ± 8.80 years of age, 297 men) with AS who underwent preoperative cardiac CT and echocardiography for AVR were included in this study. Among the total patients, 95.51% (511/535) were diagnosed as severe AS, and 4.49% (24/535) were diagnosed as moderate AS on echocardiography (Fig 2). The median follow-up period was 4.13 years, and major adverse cardiac and cerebrovascular events (MACCE) occurred in 44 (8.22%) patients (Table 1).

10.1371/journal.pone.0280530.g002 Flow chart of patient inclusion.

AS, aortic stenosis; AVR, aortic valve replacement; AVA, aortic valve area.

 10.1371/journal.pone.0280530.t001 Clinical characteristics and echocardiographic findings of study patients.
Characteristics Numbers
Age, years† 66.83 ± 8.80
Male 297 (55.51)
BSA, m2* 1.65 ± 0.17
Hypertension 291 (54.39)
DM 132 (24.67)
Atrial fibrillation 79 (14.77)
Heart failure 40 (7.48)
Aortic aneurysm 97 (18.13)
PCI or CABG 126 (23.55)
Concomitant aortic replacement 77 (14.39)
B-type natriuretic peptide, pg/mL* 343.71 ± 726.24
Blood urea nitrogen, mg/dL* 18.37 ± 8.20
Creatinine, mg/dL* 1.02 ± 0.96
Echocardiography
    LVEF, %* 59.51 ± 10.76
    Peak velocity, m/s* 4.88 ± 0.91
    Mean PG, mmHg* 60.03 ± 22.85
    LVMI, g/m2* 134.44 ± 35.61
    Aortic valve VTI, cm* 120.39 ± 28.21
    LVOT VTI, cm* 21.28 ± 4.21
    LVOT diameter, mm* 21.09 ± 1.62
    AVAecho, mm2* 64.71 ± 18.30
    ESVI, mL/m2* 28.87 ± 18.20
    EDVI, mL/m2* 67.72 ± 24.69
Systemic arterial compliance, mL/m2/mmHg* 0.80 ± 0.34
Valvulo-arterial impedance (Zva), mmHg/mL/m2* 5.21 ± 1.64
Degree of AS
    Severe AS 511 (95.51)
     High gradient severe AS 438 (81.87)
        Classic LF-LG AS 18 (3.36)
        Paradoxical LF-LG AS 55 (10.28)
        Moderate AS 24 (4.49)
CT findings
    Valve morphology
        Tricuspid 260 (48.60)
        Bicuspid with raphe 131 (24.39)
        Bicuspid without raphe 144 (26.92)
    AVA calcium score* 2894.91 ± 1845.45
    AVAplani, mm2* 90.32 ± 25. 36
    Calculated AVACT* 90.89 ± 29.51
    Aortic annulus
        Circularity, %* 81.45 ± 7.43
        Mean diameter, mm* 25.01 ± 2.66
        Perimeter, mm* 79.90 ± 8.44
        Area, mm2* 486.43 ± 102.89
         Sinus of Valsalva diameter, mm* 36.66 ± 4.57
         Sinotubular junction diameter, mm* 31.07 ± 4.74
         Ascending aorta tubular portion, mm* 40.65 ± 6.51
Surgical valve size, mm* 22.17 ± 2.12
Surgical valve type
        Bioprosthetic valve 102 (19.07)
        Mechanical valve 433 (80.93)
Follow-up duration, year* 4.13 ± 1.73
Operative mortality (30-day mortality) 8 (1.50)
MACCE including cardiovascular death 44 (8.22)
Overall mortality 74 (13.83)

Note.–Data are numbers and the percentages are in parentheses.

*Mean ± standard deviation. AS, aortic stenosis; AVA, aortic valve area; BSA, body surface area; CABG, coronary artery bypass grafting; DM, diabetes mellitus; EDVI, end-diastolic volume index; ESVI, end-systolic volume index; LF/LG, low-flow and low-gradient; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; LVOT, left ventricular outflow tract; MACCE, major adverse cardiac and cerebrovascular event; PCI, Percutaneous coronary intervention; PG, pressure gradient; VTI, velocity time integral.

 3.2. Discordance between AVA<sub>echo</sub> and AVA<sub>CT</sub> in classifying severe AS

The inter-reader agreement of the CT measurements ranged from an ICC of 89.20–98.60 (P < 0.001). The correlation between AVAecho and AVACT showed high positive correlation (r = 0.79, P < 0.001), whereas the correlation between AVAplani and AVAecho was moderate (r = 0.52, P < 0.001). The AVACT was larger than the AVAecho (0.91 ± 0.30 vs. 0.65 ± 0.18 cm2, P < 0.001) and the mean difference between AVACT and AVAecho was 0.26 cm2 (95% CI, 0.25−0.27 cm2, P < 0.001) (Fig 3). The difference between the AVACT and AVAecho also increased as the AVAecho increased (P < 0.001).

10.1371/journal.pone.0280530.g003 Bland-Altman plot of AVA<sub>echo</sub> and AVA<sub>CT</sub>.

AS, aortic stenosis; AVA, aortic valve area; SD, standard deviation.

Among the patients who were diagnosed as having severe AS by an echocardiography, 10.96% (56/511) of these patients had discordance between the AVAecho and AVACT (Table 2). Male patients were more common than female patients in the discordant group (78.57% vs. 51.87%, P < 0.001). The BSA was larger in the discordant group than in the concordant group (1.72 ± 0.16 m2 vs. 1.63 ± 0.16 m2, P = 0.001). Bicuspid AV was less frequent in the discordant group than in the concordant group (37.50% vs. 53.63%; P < 0.02). The mean AVAecho was larger in the discordant group than in the concordant group (81.68 ± 8.77 mm2 vs. 60.02 ± 13.70 mm2, P < 0.001). LF/LG AS was more frequent in the discordant group compared to the concordant group (23.21% vs. 13.19%, P = 0.04; Table 2 and S1 Table in S1 File). Peak velocity, peak pressure gradient (PG) and mean PG was lower in the discordant group than in the concordant group (for all, P < 0.05). The CT measurements of the calculated AVACT, AVAplani, annulus diameter, area, and perimeter, mean diameters of the LVOT, sinus of Valsalva, and ST junction, all were significantly larger in the discordant group than in the concordant group, both before normalization and after normalization to the BSA (P < 0.05) (Table 3). In the discordant group, the tricuspid AV was the most common valve morphology and was more frequent than the concordance group (62.50% vs. 45.38%, P = 0.01). There was no significant difference in the AVA calcium score and aortic annulus circularity between the discordant and concordant groups (P = 0.180 and P = 0.21, respectively).

10.1371/journal.pone.0280530.t002 Clinical and echocardiographic characteristics of concordant and discordant groups between AVA values measured by echocardiography and CT in severe AS.
Characteristics Concordant group (n = 455) Discordant group (n = 56) P value
AVAecho <1.0 cm2 and AVACT <1.2 cm2 AVAecho <1.0 cm2 and AVACT ≥1.2 cm2
Age, years* 66.84 ± 8.80 67.11 ± 8.61 0.83
Male 236 (51.87) 44 (78.57) < 0.001
BSA, m2* 1.63 ± 0.16 1.72 ± 0.16 0.001
Hypertension 240 (52.75) 33 (58.93) 0.38
Atrial fibrillation 65 (14.29) 8 (14.29) > 0.99
PCI or CABG 106 (23.30) 11 (19.64) 0.85
Rheumatic valvular disease 46 (10.11) 2 (3.57) 0.15
B-type natriuretic peptide, pg/mL† 106.00 (48.00–287.50) 63.00 (31.00–254.00) 0.13
Echocardiography
    LVEF, %* 59.83 ± 10.54 58.71 ± 11.54 0.46
    Peak velocity, m/s* 4.98 ± 0.89 4.63 ± 0.74 0.004
    Peak PG, mmHg* 101.82 ± 35.89 87.54 ± 56.82 0.004
    Mean PG, mmHg* 62.12 ± 22.97 52.30 ± 17.60 0.002
    LVMI, g/ m2* 135.05 ± 36.0 132.38 ± 35.31 0.60
    AV VTI, cm* 125.24 ± 26.63 97.58 ± 19.14 < 0.001
    LVOT VTI, cm* 21.09 ± 4.17 22.01 ± 4.05 0.12
    LVOT diameter, mm* 21.02 ± 1.52 21.29 ± 1.51 0.20
    LVOT diameter/BSA, mm* 12.96 ± 1.33 12.47 ± 1.11 0.008
    AVAecho, mm2* 60.02 ± 13.70 81.68 ± 8.77 < 0.001
    ESVI, mL/m2* 28.37 ± 17.91 30.68 ± 19.07 0.37
    EDVI, mL/m2* 67.21 ± 23.35 70.49 ± 26.52 0.08
    SAC, mL/m2/mmHg* 0.81 ± 0.34 0.76 ± 0.28 0.26
    Valvulo-arterial impedance (Zva), mmHg/mL/m2* 5.24 ± 1.64 5.06 ± 1.66 0.43
Subgroups 0.04
    Severe AS 395 (86.81) 43 (76.79) 0.04‡
    Classic LF-LG AS 13 (2.86) 5 (8.93)
    Paradoxical LF-LG AS 47 (10.33) 8 (14.29)
Surgical valve size, mm* 21.99 ± 2.09 23.32 ± 1.76 < 0.001
Postoperative findings
    LVEF, %* 59.64 ± 9.35 56.82± 9.41 0.04
    Peak velocity, m/s* 2.65 ± 0.58 2.40 ± 0.66 0.004
    Peak PG, mmHg* 28.41 ± 10.92 24.15 ± 11.14 0.008
    Mean PG, mmHg* 15.77 ± 6.70 13.46 ± 6.39 0.02
    LVMI, g/m2* 114.41 ± 31.17 118.18 ± 35.92 0.41
    MACCE 36 (7.91) 7 (12.50) 0.24
    Overall mortality 63 (13.85) 8 (14.30) 0.93

Note.–Data are numbers and the percentages in parentheses.

*Data are mean ± standard deviation.

†Data are median and the interquartile range in parentheses.

‡Comparison between patients with severe AS and LF/LG AS (classic or paradoxical). AS, aortic stenosis; AVA, aortic valve area; BSA, body surface area; CABG, coronary artery bypass graft; EDVI, end-diastolic volume index; ESVI, end-systolic volume index; LF/LG, low-flow and low-gradient; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; LVOT, left ventricular outflow tract; MACCE, major adverse cardiac and cerebrovascular event; PCI, percutaneous coronary intervention; PG, pressure gradient; SAC, systemic arterial compliance; VTI, velocity time integral.

 10.1371/journal.pone.0280530.t003 CT findings of concordant and discordant groups between AVA values measured by echocardiography and CT in severe AS.
CT findings Concordant group (n = 455) Discordant group (n = 56) P value
AVAecho <1.0 cm2 and AVACT <1.2 cm2 AVAecho <1.0 cm2 and AVACT ≥1.2 cm2
Valve morphology 0.011
    Tricuspid (%) 211 (45.38) 35 (62.50)
    Bicuspid with raphe (%) 133 (28.60) 6 (10.71)
    Bicuspid without raphe (%) 111 (23.87) 15 (26.79)
LVOT mean diameter* 24.62 ± 2.82 26.59 ± 2.69 < 0.001
AVA calcium score† 2747.90 (1523.28–4153.45) 2229.95 (1422.80–3734.95) 0.18
ln(AVA calcium score)† 7.92 (7.33–8.33) 7.71 (7.26–8.23) 0.18
AVAplani, mm2* 86.20 ± 22.53 109.16 ± 26.04 < 0.001
AVACT, mm2* 82.06 ± 18.95 136.85± 26.71 < 0.001
Aortic annulus
    Circularity, %* 81.66 ± 7.49 81.34 ± 7.95 0.21
    Maximal dimeter, mm* 27.21 ± 3.06 30.42 ± 3.04 < 0.001
    Mean diameter, mm* 24.67 ± 2.52 27.38 ± 2.46 < 0.001
    Perimeter, mm* 78.92 ± 8.08 86.82 ± 7.97 < 0.001
    Area, mm2* 474.67 ± 96.84 570.70 ± 110.80 < 0.001
    Sinus of Valsalva diameter, mm* 36.34 ± 4.56 39.09 ± 4.01 < 0.001
    Sinotubular junction diameter, mm* 30.82 ±4.74 32.64 ± 4.36 0.007
    Ascending aorta tubular portion, mm* 40.58 ± 6.31 40.83 ± 7.07 0.79
Measurements normalized to BSA
    AVAplani, mm2* 52.97 ± 13.70 64.27 ± 16.97 < 0.001
    AVACT, mm2* 50.34 ± 11.27 80.03 ± 20.64 < 0.001
    Aortic annulus
        Maximal dimeter, mm* 16.74 ± 1.95 17.80 ± 1.92 < 0.001
        Mean diameter, mm* 15.18 ± 1.65 16.02 ± 1.53 < 0.001
        Perimeter, mm* 48.56 ± 5.22 50.80 ± 4.85 0.002
        Area, mm2* 290.89 ± 54.29 332.28 ± 55.43 < 0.001
    Sinus of Valsalva diameter, mm* 22.37 ± 2.92 22.88 ± 2.50 0.21
    Sinotubular junction diameter, mm* 18.97 ± 2.98 19.10 ± 2.65 0.76
    Ascending aorta tubular portion, mm* 25.02 ± 4.29 23.93 ± 4.47 0.07

Note.–Data are numbers and the percentages in parentheses.

*Data are mean ± standard deviation.

†Data are median and the interquartile range in parentheses. AS, aortic stenosis; AVA, aortic valve area; BSA, body surface area; LVOT, left ventricular outflow tract.

Among the patients who were diagnosed as moderate AS on echocardiography, 16.67% (4/24) of these patients showed discordance between the AVAecho and AVACT (AVAecho ≥1.0 cm2 and AVACT <1.2 cm2). The median AVACT was 151.45 mm2 (IQR: 140.61–179.24) for the concordant group and 108.88 mm2 (IQR: 103.07–114.68) for the discordant group, which was significantly smaller in the discordant group (P = 0.002). The discordant group showed higher LVEF and AV VTI, lower end-systolic volume index, and smaller perimeter and area of the aortic annulus (for all, P < 0.05) (S2 Table in S1 File).

 3.3. Factors associated with the discordance between AVA<sub>echo</sub> and AVA<sub>CT</sub>

The univariable logistic regression analysis indicated that male sex, BSA, peak velocity, peak PG, mean PG, AV VTI, normalized LVOT, AVAecho, LF/LG AS, tricuspid AV, normalized AVACT both normalized and unnormalized AVAplani, aortic annulus measurements (diameter, perimeter, annulus area) and diameters of sinus of Valsalva and ST junction were significant factors associated with the discordance between the AVAecho and AVACT (P < .05) in patients with severe AS (AVAecho <1.0 cm2) (Table 4). In the multivariable analysis, BSA (odds ratio [OR]: 68.03, 95% confidence interval [CI]:5.45–849.99; P = 0.001), AVAecho (OR: 1.19, 95%CI:1.14–1.24; P < .001), tricuspid valve morphology (OR: 2.83, 95%CI:1.23–6.50; P = 0.01) and the annulus area normalized to the BSA (OR: 1.02, 95%CI:1.02–1.03; P < 0.001) were significant independent factors for the discordance between the AVAecho and AVACT (Table 5). The optimal cut-offs for predicting discordance between the AVAecho and AVACT were > 1.74 m2 for the BSA (AUC: 0.65, sensitivity: 46.43%, specificity: 76.26%), > 73.44 mm2 for the AVAecho (AUC: 0.91 sensitivity: 83.93%, specificity: 84.18%), and > 305.50 mm2 for annulus area normalized to BSA (AUC: 0.72, sensitivity: 73.21%, specificity: 67.03%).

10.1371/journal.pone.0280530.t004 Univariate logistic regression analysis of clinical and CT characteristics to predict the discordance between the aortic valvular areas measured by echocardiography and CT.
Variables OR (95% CI) P value
Age, years 1.00 (0.97–1.04) 0.83
Male 3.40 (1.75–6.61) < 0.001
BSA, m2 21.1 (3.36–132.6) 0.001
Echocardiography
    Peak velocity, m/s 0.64 (0.46–0.87) 0.005
    Peak PG 0.99 (0.97–1.00) 0.004
    Mean PG 0.98 (0.97–0.99) 0.002
    AV VTI, cm 0.95 (0.93–0.96) < 0.001
    LVOT diameter/BSA, mm 0.74 (0.59–0.93) 0.009
AVAecho, cm2 1.15 (1.11–1.19) < 0.001
LF/LG AS (reference: severe AS) 1.99 (1.01–3.92) 0.05
CT findings
    Tricuspid morphology (reference: bicuspid) 1.93 (1.09–3.41) 0.02
    LVOT mean diameter, mm 1.27 (1.15–1.40) < 0.001
    AVAplani, cm2 1.04 (1.03–1.05) < 0.001
    Aortic annulus mean diameter, mm 1.47 (1.31–1.64) < 0.001
    Aortic annulus maximal diameter, mm 1.34 (1.22–1.47) < 0.001
    Aortic annulus perimeter, mm 1.12 (1.08–1.16) < 0.001
    Aortic annulus area, mm2 1.01 (1.01–1.01) < 0.001
    Sinus of Valsalva diameter 1.14 (1.07–1.21) < 0.001
    Sinotubular junction diameter, mm 1.08 (1.02–1.13) 0.008
    Normalized to BSA
        AVAplani/BSA, mm2* 1.05 (1.03–1.07) < 0.001
    AVACT/BSA, mm2* 1.26 (1.19–1.34) < 0.001
    Aortic annulus
        Maximal dimeter/BSA, mm* 1.29 (1.13–1.47) < 0.001
        Mean diameter/BSA, mm* 1.35 (1.14–1.59) < 0.001
        Perimeter/BSA, mm* 1.08 (1.03–1.14) 0.003
        Area/BSA, mm2* 1.01 (1.01–1.02) < 0.001

AV, aortic valve; AVA, aortic valve area; BSA, body surface area; CI, confidence interval; LF/LG, low-flow and low-gradient; LVOT, left ventricular outflow tract; OR, odds ratio; PG, pressure gradient; VTI, velocity time integral.

 10.1371/journal.pone.0280530.t005 Multivariable logistic regression analysis of clinical and CT characteristics to predict the discordance between the aortic valvular areas measured by echocardiography and CT.
OR (95%CI) P value
BSA, m2 68.03 (5.45–849.99) 0.001
AVAehco, cm2 1.19 (1.14–1.24) < 0.001
Tricuspid morphology (reference: bicuspid) 2.83 (1.23–6.50) 0.014
Annulus area normalized to BSA 1.02 (1.02–1.03) < 0.001

AVA, aortic valve area; BSA, body surface area; CI, confidence interval; OR, odds ratio.

 4. Discussion

Our study demonstrated that 10.96% (56/511) of patients with severe AS based on echocardiography showed discordant grading of severe AS between echocardiography and CT. Patients with larger BSA, AVAecho, tricuspid valve morphology, and annulus area normalized to the BSA were significant factors that were associated with the discordant grading of AVA between echocardiography and CT. The combined use of CT and echocardiography for grading severe AS should be emphasized and might be helpful in these patients.

As demonstrated by Clavel et al., the AVACT was larger than the AVAecho, and larger cut-point of 1.2 cm2 should be used for grading severe AS on CT [13]. Although we applied the larger cut-point of 1.2 cm2 for grading severe AS on CT compared to the cut-point of 1.0 cm2 on echocardiography, 10.96% of patients showed discordance between grading of severe AS on the CT and echocardiography. Although it is unknown which modality can more accurately grade severe AS in the discordant group, changes from the diagnosis of severe AS on the echocardiography to moderate AS by CT may affecting the timing of AV surgery or intervention.

Inaccurate measurements of the LVOT diameters on echocardiography and low stroke volume can affecting the inconsistent grading of severe AS [18]. In a previous study, 52% of normal flow–low gradient and 12% of LF/LG severe AS are reclassified into moderate AS [18]. In our study, LF/LG AS was also more frequent in the discordant group than in the concordant group (23.21% vs. 13.19%; P = 0.04). Implementation of CT scans may be the important discriminatory method between true severe and moderate AS by minimizing the inaccurate measurements of AVA due to artifacts on the echocardiography from leaflet calcifications or anatomical assumptions of a circular shape of the LVOT in two-dimensional echocardiography along with stress echocardiography [19].

It has been suggested that the use of AVAecho index to the BSA for patients with either unusually small or large body sizes. However, indexing for body size is controversial primarily because the current algorithms for defining body size, such as the BSA, do not necessarily reflect the normal AVA in obese patients because the valve area does not increase with body size. Therefore, the AVA index can be underestimated in patients with a large BSA. In our study, large BSA and large EDVI suggested that large heart size was a significant factor in the discordance between AVAecho and AVACT in grading severe AS. In these patients, measurement errors that may cause underestimation of the AVA, PG, and flow on the echocardiography could be prudentially re-evaluated with the combined use of CT [20].

In this study, the correlation between AVAecho and AVACT showed a high positive correlation, whereas the correlation between AVAplani and AVAecho was moderate (r, 0.79 vs. 0.52). As a result of this finding, we further defined discordant and concordant groups based on AVACT by the continuity equation rather than AVAplani. Accurately measuring AVA using a planimetry approach is limited due to the difficulty in drawing the maximal systolic opening area on 2D-thin slice thickness images as the tips of the aortic cusps are not contained to one 2D plane. On the other hand, using thick slice thickness images for planimetry area measurements makes it challenging to outline the margin of cusps due to the blurring of images which can lead to overestimating the valve opening area. Therefore, calculating AVA by incorporating velocity information from echocardiography and the size of LVOT on high spatial resolution cardiac CT images based on continuity equations can be more accurate to reflect the maximal systolic opening of AV.

Our study has several limitations. Firstly, the prognostic implications of the discordance between AVACT and AVAecho could not be addressed in this study. This resulted from the discordant results between CT and echocardiography not being considered when determining the timing of AVR. Furthermore, as echocardiography was the standard exam, the effect of discrepancies between two modalities on the patients outcome could not be evaluated. Secondly, our cohort was limited to patients who underwent AVR and therefore does not evaluate the effect on mortality due to the natural course of disease according to AS severity. As our study included patients with only a narrow higher end (severe) of AS, as opposed to the lower end (mild) of AS, this can cause selection bias. Future studies focusing on assessing the modality of choice to establish the optimal time of surgery and the effect of AS severity grading using these different modalities would be of value in order to determine the clinical outcome of medical management compared to surgery. Second, we were not able to consider the effect of dynamic changes in the diameter of LVOT on measurement variability of AVAecho, as the LVOT diameter measured during the mid-systolic phase was used for calculating the AVAecho. Third, in this study, since the echocardiography or CT data were collected from the actual clinical records, AV morphology was described based on the previously described classification by Sievers et al [21]. However, the recently suggested new classification of AV morphology subclassified fused, 2-sinus, and partial fusion type of bicuspid AV [22]. However, little is known about whether the new classification is better or not to predict outcome in patients with AS. Future studies with the new classification of AVs would have a value.

 5. Conclusion

Larger BSA, AVAecho, tricuspid valve morphology, and annulus size were associated with discordance between grading severe AS based on AVA on echocardiography and CT. The combined use of CT and echocardiography for grading AS should be emphasized and will be helpful in these patients.

 Supporting information <p>(DOCX)</p> </caption> </supplementary-material> </sec> </body> <back> <glossary> <title>Abbreviations AS

aortic stenosis

 AUC

areas under the receiver operating characteristic curve

 AVA

aortic valve area

 AVR

aortic valve replacement

 BSA

body surface area

 BNP

B-type natriuretic peptide

 CT

computed tomography

 DLP

dose length product

 ED

effective dose

 ICC

intraclass correlation

 IQR

interquartile range

 LF/LG

low-flow/low-gradient

 LVOT

left ventricular outflow tract

 PG

pressure gradient

 TAVR

transcatheter aortic valve replacement

 TTE

transthoracic echocardiography

 VTI

velocity time integral

 References Rosenhek R, Zilberszac R, Schemper M, Czerny M, Mundigler G, Graf S, et al. Natural history of very severe aortic stenosis. Circulation. 2010;121(1):151–6. doi: 10.1161/CIRCULATIONAHA.109.894170 20026771 Clavel MA, Magne J, Pibarot P. Low-gradient aortic stenosis. Eur Heart J. 2016;37(34):2645–57. doi: 10.1093/eurheartj/ehw096 27190103 Carabello BA. Should severe aortic stenosis be operated on before symptom onset? Aortic valve replacement should be operated on before symptom onset. Circulation. 2012;126(1):112–7. doi: 10.1161/CIRCULATIONAHA.111.079350 22753532 Kang DH, Park SJ, Lee SA, Lee S, Kim DH, Kim HK, et al. Early Surgery or Conservative Care for Asymptomatic Aortic Stenosis. The New England journal of medicine. 2020;382(2):111–9. doi: 10.1056/NEJMoa1912846 31733181 Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, 3rd, Guyton RA, et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(23):2440–92. doi: 10.1161/CIR.0000000000000029 24589852 Santos N, de Agustin JA, Almeria C, Goncalves A, Marcos-Alberca P, Fernandez-Golfin C, et al. Prosthesis/annulus discongruence assessed by three-dimensional transoesophageal echocardiography: a predictor of significant paravalvular aortic regurgitation after transcatheter aortic valve implantation. Eur Heart J Cardiovasc Imaging. 2012;13(11):931–7. doi: 10.1093/ehjci/jes072 22511810 Alkadhi H, Wildermuth S, Plass A, Bettex D, Baumert B, Leschka S, et al. Aortic stenosis: comparative evaluation of 16–detector row CT and echocardiography. Radiology. 2006;240(1):47–55. doi: 10.1148/radiol.2393050458 16709791 Bouvier E, Logeart D, Sablayrolles J-L, Feignoux J, Scheublé C, Touche T, et al. Diagnosis of aortic valvular stenosis by multislice cardiac computed tomography. European heart journal. 2006;27(24):3033–8. doi: 10.1093/eurheartj/ehl273 17015404 Leborgne L, Choplin Y, Renard C, Claeys M, Levy F, Jarry G, et al. Quantification of aortic valve area with ECG-gated multi-detector spiral computed tomography in patients with aortic stenosis and comparison of two image analysis methods. International journal of cardiology. 2009;135(2):266–9. doi: 10.1016/j.ijcard.2008.03.095 18619692 Feuchtner GM, Müller S, Bonatti J, Schachner T, Velik-Salchner C, Pachinger O, et al. Sixty-four slice CT evaluation of aortic stenosis using planimetry of the aortic valve area. American Journal of Roentgenology. 2007;189(1):197–203. doi: 10.2214/AJR.07.2069 17579171 Saitoh T, Shiota M, Izumo M, Gurudevan SV, Tolstrup K, Siegel RJ, et al. Comparison of left ventricular outflow geometry and aortic valve area in patients with aortic stenosis by 2-dimensional versus 3-dimensional echocardiography. The American journal of cardiology. 2012;109(11):1626–31. doi: 10.1016/j.amjcard.2012.01.391 22440128 Utsunomiya H, Yamamoto H, Horiguchi J, Kunita E, Okada T, Yamazato R, et al. Underestimation of aortic valve area in calcified aortic valve disease: effects of left ventricular outflow tract ellipticity. Int J Cardiol. 2012;157(3):347–53. doi: 10.1016/j.ijcard.2010.12.071 21236506 Clavel MA, Malouf J, Messika-Zeitoun D, Araoz PA, Michelena HI, Enriquez-Sarano M. Aortic valve area calculation in aortic stenosis by CT and Doppler echocardiography. JACC Cardiovasc Imaging. 2015;8(3):248–57. doi: 10.1016/j.jcmg.2015.01.009 25772832 Halpern EJ, Mallya R, Sewell M, Shulman M, Zwas DR. Differences in aortic valve area measured with CT planimetry and echocardiography (continuity equation) are related to divergent estimates of left ventricular outflow tract area. American Journal of Roentgenology. 2009;192(6):1668–73. doi: 10.2214/AJR.08.1986 19457833 Pouleur AC, le Polain de Waroux JB, Pasquet A, Vancraeynest D, Vanoverschelde JLJ, Gerber BL. Planimetric and continuity equation assessment of aortic valve area: head to head comparison between cardiac magnetic resonance and echocardiography. Journal of Magnetic Resonance Imaging: An Official Journal of the International Society for Magnetic Resonance in Medicine. 2007;26(6):1436–43. doi: 10.1002/jmri.21182 17968960 Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification. European journal of echocardiography. 2006;7(2):79–108. doi: 10.1016/j.euje.2005.12.014 16458610 Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. 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. Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography. 2005;18(12):1440–63. doi: 10.1016/j.echo.2005.10.005 16376782 Kamperidis V, van Rosendael PJ, Katsanos S, van der Kley F, Regeer M, Al Amri I, et al. Low gradient severe aortic stenosis with preserved ejection fraction: reclassification of severity by fusion of Doppler and computed tomographic data. European Heart Journal. 2015;36(31):2087–96. doi: 10.1093/eurheartj/ehv188 26033985 Clavel MA, Ennezat PV, Maréchaux S, Dumesnil JG, Capoulade R, Hachicha Z, et al. Stress echocardiography to assess stenosis severity and predict outcome in patients with paradoxical low-flow, low-gradient aortic stenosis and preserved LVEF. JACC Cardiovasc Imaging. 2013;6(2):175–83. doi: 10.1016/j.jcmg.2012.10.015 23489531 Baumgartner H, Hung J, Bermejo J, Chambers JB, Edvardsen T, Goldstein S, et al. Recommendations on the echocardiographic assessment of aortic valve stenosis: a focused update from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. European Heart Journal—Cardiovascular Imaging. 2016;18(3):254–75. Sievers HH, Schmidtke C. A classification system for the bicuspid aortic valve from 304 surgical specimens. The Journal of thoracic and cardiovascular surgery. 2007;133(5):1226–33. doi: 10.1016/j.jtcvs.2007.01.039 17467434 Michelena HI, Della Corte A, Evangelista A, Maleszewski JJ, Edwards WD, Roman MJ, et al. International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes. The Journal of thoracic and cardiovascular surgery. 2021;162(3):e383–e414. doi: 10.1016/j.jtcvs.2021.06.019 34304896 10.1371/journal.pone.0280530.r001 Decision Letter 0 Wang Tom Kai Ming Academic Editor 2023 Tom Kai Ming Wang This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 0

7 Oct 2022

PONE-D-22-24629Differences in Aortic Valve Area Measured on Cardiac CT and Echocardiography in Patients with Aortic StenosisPLOS ONE

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Additional Editor Comments:

Thanks for your submission. In addition to reviewer comments below (or to repeat), please address the following questions/comments:

1. It appears the vast majority of patients at your hospital undergoing surgical AVR had pre-op cardiac CT with multiphase. Explain the rationale of this practice and specific benefits - most centers probably only do single phase pre-op cardiac CT, unless it is for TAVI workup. Also explain reasons why some patients didn’t get CT or multiphase CT (perhaps CKD)?

2. Were everybody with having AVR included in this study, or just those having isolated AVR. Was severe aortic stenosis an inclusion criteria? Was prior AVR, cardiac surgery, or endocarditis excluded? Explain the definition of concomitant significant AR (is this moderate or higher, or severe or higher, and how was this graded qualitative or quantitative)? Put in the limitations the selection bias that we are dealing with only a narrow higher end of aortic stenosis not the lower end.

3. Explain what method was used to calculate AVA on echo – was it continuity equation with VTI or peak velocity, how was stroke volume calculated (LVOT-VTI method or LVEDV-LVESV), or even planimetry. Continuity methods are expected to have discrepancy with anatomical methods for AVA, in addition to echo and CT having different measurements – please comment on these differences in the discussion.

4. You defined classic and paradoxical low flow low gradient AS in your methods along with severe AS and moderate AS – please present baseline/echo parameters in table 1 based on these subgroups also. Was there an association between the LFLG AS subgroups and AVA discordance discordance? What about calcium score (which can distort AVA-CT measurement) is it associated with the AVA discordance?

5. Add the following characteristics to table 1: diabetes, coronary heart disease, aortic aneurysm, NYHA class, echo: LVSVi, dimensionless index, LAVi, RVSP, RV function, CT: LVEDVi, LVESVi, LVSVi, LVEF; bioprosthetic or mechanical AVR, concomitant surgery, operative mortality (30-days).

6. In the Bland-Altman plot figure, please use average AVA echo and ct in the X axis.

7. 6. Another figure illustrating the AVAecho and AVA CT technique used would be appreciated for the journal’s medical audience.

8. Perform multivariable analysis of clinical, echo and CT parameters to predict overall mortality during follow-up (remember up to 7 covariates given 74 mortality events). Was CT valve parameters stronger predictor than echo?

9. Have a paragraph before limitations in the discussion called clinical implications. What are the main implications for your study? When and how do you recommend CT-AVA be used and what thresholds for severe? How does your study change current management?

10. Any items you can’t address above need to add to limitations.

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: 1-Retrospective study.

2- Data collected from medical records

3-Methods section lacks details on how the AoVA by CT was calculated. Did the authors used the CT maximal LVOT diameter, average area or planimetered LVOT area?.

4-Discordant valve area was defined when the difference between echo and CT was>0.2cm2. This occurred in a relatively small number of patients.

5-As in prior studies AV by CT was largen than echo AoVA.

6-The main objective of the study was to find the determinants form discrepant AoVA

7-In the bland Altman plot shown, the X axis shows the echo AoVA and not the average of Echo and CT as is tipically done.

8-Not clear what the unique contribution to this paper compared to similar ones that already exist in the literature.

Reviewer #2: The manuscript entitled "Differences in Aortic Valve Area Measured on Cardiac CT and Echocardiography in Patients with Aortic Stenosis" by Koo. et al. aimed to compare the aortic valve area AVA measured on CT and echocardiography, and demonstrate the factors that lead to discordant AVA readings between CT and echocardiography. From the 781 retrospectively selected patients, 95.51% were documented to have echocardiographic severe aortic stenosis and 10.96% of those had discordance between AVAecho and AVACT. Larger BSA, AVAecho, tricuspid AV morphology and indexed annulus area were associated with AVA discordance between echo and CT.

The authors have done a lot of work in collating this information and improving our knowledge in multimodality AS classification with few clarifications requested.

1. It should be highlighted in the text that the main comparison between AVAecho and AVACT utilizes continuity equation for both and thus are comparisons of an echo solely or a hybrid approach. This said, a hybrid approach measurement can also be simplified to the comparison of annular area in both modalities.

2. Furthermore, the discussion section sheds less light on AVAplani as a comparison and thus is confusing as the norm of a CT approach is usually to check planimetry area measurements. If that is not the case, it is then important to emphasize the differences within CT measurements whether measurement have been taken by the hybrid approach or by planimetry.

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Reviewer #2: No

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Submitted filename: Peer Review - PLOS ONE -Ossama Abou Hassan Oct 2022.docx

 10.1371/journal.pone.0280530.r002 Author response to Decision Letter 0 Submission Version 1

19 Dec 2022

Point-by-point response to reviewers

Submission ID: PONE-D-22-24629

Manuscript title: "Differences in Aortic Valve Area Measured on Cardiac CT and Echocardiography in Patients with Aortic Stenosis"

In response to the reviewer’s comments, we have attempted to follow the editors and reviewer’s recommendations to our best ability. We have addressed several important matters that the reviewers raised, and we have revised the manuscript appropriately. We hope that our responses and revisions will alleviate the reviewers concerns and we would like to thank you for taking the time to review our manuscript.

Editor’s comments

Thanks for your submission. In addition to reviewer comments below (or to repeat), please address the following questions/comments:

E-1. It appears the vast majority of patients at your hospital undergoing surgical AVR had pre-op cardiac CT with multiphase. Explain the rationale of this practice and specific benefits - most centers probably only do single phase pre-op cardiac CT, unless it is for TAVI workup. Also explain reasons why some patients didn’t get CT or multiphase CT (perhaps CKD)?

Response: In our center, for baseline work up in patients with aortic valvular disease, multiphase CT is routinely used as a preoperative cardiac CT. Multiphase data can provide information regarding the exact motion of aortic leaflets as well as morphological information regarding the aortic root. Echocardiography may be sufficient in terms of determining AS severity, but as demonstrated in our study, in certain patients, echocardiography could be insufficient and prudentially re-evaluated with the combined use of CT. Although this cohort is a group of patients who underwent AVR, for patients with symptomatic AS that require intervention including surgical or procedural treatment, cardiac CT is routinely performed prior to making the decision between surgery or TAVI because CT findings are also important in determining those treatment options. Intraoperative valve sizing can be done by inserting a sizer directly in the aortic root, however, preoperative sizing on systolic phase CT data is useful for narrowing down as for a preliminary selection. Therefore, in our center, we usually perform multiphase cardiac CT with a 20% tube current modulation (dose pulsing windows, 20%–70% of the R-R interval) to minimize the radiation dose in patients with valvular heart disease. Those patients who were excluded from our cohort due to unavailable multiphase data were patients who underwent only single-phase cardiac CT for the purpose of evaluation of coronary artery disease, rather than valvular disease, or patients with missing multiphase data in our database storage. We provided additional description in the Materials and Methods for the rationale of performing multiphase cardiac CT in our center.

Revised manuscript:

In our center, for baseline work up in patients with aortic valvular disease, multiphase cardiac CT is routinely performed prior to making the decision between surgery or TAVR as multiphase cardiac CT can provide information regarding the exact motion of aortic leaflets as well as morphological information regarding the aortic root and those CT findings are also important in determining those treatment options. Retrospective electrocardiogram-gated scanning was performed with a 20% tube current modulation (dose pulsing windows, 20%–70% of the R-R interval) to minimize the radiation dose.

E-2. Were everybody with having AVR included in this study, or just those having isolated AVR. Was severe aortic stenosis an inclusion criteria? Was prior AVR, cardiac surgery, or endocarditis excluded? Explain the definition of concomitant significant AR (is this moderate or higher, or severe or higher, and how was this graded qualitative or quantitative)? Put in the limitations the selection bias that we are dealing with only a narrow higher end of aortic stenosis not the lower end.

Response: In this study, patients who underwent surgical AVR due to symptomatic moderate to severe AS were consecutively included. Among the total included patients, 95.51% (511/535) were diagnosed as severe AS, and 4.49% (24/535) were diagnosed as moderate AS based on echocardiography.

Patients with AVR alone were searched from the electronic surgical records. Patients who previously underwent valvular surgeries were initially excluded. Then, patients with endocarditis (n = 11) or concomitant significant aortic regurgitation (AR) (n = 177) were excluded and significant AR was qualitatively defined as moderate or high degree based on echocardiographic findings. As patients usually underwent multiphase cardiac CT for preprocedural or presurgical evaluation, most patients who do not have AS or have a mild degree of AS do not undergo multiphase cardiac CT in clinical practice. Moreover, we also agree with your comment, that in our study cohort which included patients who underwent AVR, but only those with a narrow higher end of aortic stenosis (AS), not the lower end of AS. We included this point as a study limitation as it can lead to selection bias and the study results must be interpretated tentatively.

Revised manuscript (Methods): Exclusion criteria included patients with concomitant significant aortic regurgitation (qualitatively defined as moderate or higher degree based on echocardiographic findings; n = 177), [ÿ]

Revised manuscript (Discussion): As our study included patients with only a narrow higher end of AS, as opposed to the lower end of AS, this can cause selection bias. Therefore, caution is needed when interpreting the study results.

E-3. Explain what method was used to calculate AVA on echo – was it continuity equation with VTI or peak velocity, how was stroke volume calculated (LVOT-VTI method or LVEDV-LVESV), or even planimetry. Continuity methods are expected to have discrepancy with anatomical methods for AVA, in addition to echo and CT having different measurements – please comment on these differences in the discussion.

Response: Thank you for your comment. We agree with what you have discussed. AVA on echocardiography was calculated using a continuity equation with VTI. We added an additional description for the AVAecho and AVACT in our revised manuscript. AVACT was also calculated by using a hybrid method incorporating information from both echocardiography and CT, with the LVOT area measured on CT in the continuity equation with VTI at LVOT and transaortic flow on echocardiography (AVACT = LVOTCT × VTILVOT/VTIAo). For the LVOT area, a circular LVOT area was estimated by πr2 using an average diameter.

Revised manuscript (Methods):

The maximal and mean pressure gradients (PG) across the AV were estimated using a modified Bernoulli equation, and the AVA was calculated from the continuity equation with VTI (AVAecho). [ÿ]

AVACT was calculated by using the LVOT area measured on CT (LVOT area approximated by πr2 with the average diameter used for r) in the continuity equation with VTI at LVOT and transaortic flow on echocardiography (a hybrid of measures from both CT and echocardiography; AVACT = LVOTCT × VTILVOT/VTIAo).

E-4. You defined classic and paradoxical low flow low gradient AS in your methods along with severe AS and moderate AS – please present baseline/echo parameters in table 1 based on these subgroups also. Was there an association between the LFLG AS subgroups and AVA discordance? What about calcium score (which can distort AVA-CT measurement) is it associated with the AVA discordance?

Response: Thank you for your comment. The echocardiographic parameters based on the Degree of AS (Severe AS [high-gradient severe AS, classic LF-LG AS and paradoxical LF-LG AS] and moderate AS) and related subgroups are demonstrated below. This table was included as a Supplementary table in our revised manuscript for clarity.

Among the patients with severe AS (n = 511), the discordant group was more frequent in patients with LF-LG AS compared with those with high-gradient severe AS (P = 0.04; Table 2 and Supplementary Table 1 in revised manuscript). In Table 3, no significant difference was observed between concordant and discordant groups in terms of AVA calcium score (2747.90 [IQR, 1523.28 – 4153.45] vs. 2229.95 [1422.80 – 3734.95]; P = 0.18). The AVA calcium score which was calculated at the burden of calcification at the level of valve and the aortic cusps and does not appear to have a direct effect on the discordancy between AVACT or AVAecho. This is likely due to both measure areas being based on the continuity equation by applying the value of LVOT level on CT or echocardiography.

E-5. Add the following characteristics to table 1: diabetes, coronary heart disease, aortic aneurysm, NYHA class, echo: LVSVi, dimensionless index, LAVi, RVSP, RV function, CT: LVEDVi, LVESVi, LVSVi, LVEF; bioprosthetic or mechanical AVR, concomitant surgery, operative mortality (30-days).

Response: Thank you for your comment. We have added additional clinical information (diabetes, coronary heart disease, aortic aneurysm, concomitant surgery and valve type) in Table 1. Operative mortality (30-day mortality) was found to be 1.5% (8/535).

We apologize that unfortunately we do not have available information for the other characteristics you mentioned above, NYHA class, RV function and LV function on echocardiography and/or CT.

 

E-6. In the Bland-Altman plot figure, please use average AVA echo and CT in the X axis.

Response: We thought it would be more informative to demonstrate the X axis with the absolute value of echocardiography rather than the mean of two modalities. In our revised manuscript, we have replaced the new Bland-Altman plot displaying the X axis with the average for echo and CT as below.

Revised manuscript (Figure 3): Bland-Altman plot of AVAecho and AVACT (with the X-axis showing the mean of measures from echocardiography and CT).

E-7. Another figure illustrating the AVAecho and AVA CT technique used would be appreciated for the journal’s medical audience.

Response: We followed your comment and add a figure (Figure 2) illustrating the measurement of AVAecho and AVCCT used in this study.

Revised manuscript (Figure 2):

Figure 2. An example of aortic valve area (AVA) measurement using echocardiography or CT in a 74-year-old male who diagnosed as severe stenosis of fused bicuspid aortic valve.

AVA, aortic valve area; LVOT, left ventricular outflow tract; VTI, velocity time integral.

E-8. Perform multivariable analysis of clinical, echo and CT parameters to predict overall mortality during follow-up (remember up to 7 covariates given 74 mortality events). Was CT valve parameters stronger predictor than echo?

Response: Thank you for your comment. As recommended, we have performed an analysis using Cox proportional hazard models for the prognostic value of echo and CT parameters. However, both AVAecho and AVACT did not show a significant prognostic value for predicting either overall mortality or MACCE adjusted by age, sex and history of PIC or CABG (AVAecho: adjusted HR, 1.00 [95%CI, 0.99−1.01], P = .549; AVACT: adjusted HR, 1.01 [95%CI, 1.00−1.01], P = .080; AVAplani: adjusted HR, 1.00 [95%CI, 0.99−1.01], P = .561; discordant group: adjusted HR, 1.25 [95%CI, 0.68−2.32], P = .472;). These results may be due to the fact that our cohort is limited to patients who underwent AVR and therefore does not evaluate the effect on mortality due to the natural course of disease according to AS severity. In addition, patients with mild AS were excluded from the study cohort which may also limit the scope of the results.

In a previous study carried out by Clavel et al. (Reference 13), AVAecho or AVACT were independently predictive (hazard ratio [HR]: 1.26, 95% confidence interval [CI]: 1.13 to 1.42; P < 0.0001 or HR: 1.18, 95% CI: 1.09 to 1.29 per 0.10 cm2 decrease; P < 0.0001) with a similar prognostic value in patients with isolated calcific AS. Therefore, we believe in future studies, a comprehensive evaluation would be valuable and in fact required, in order to grade the effect of AS severity using different modalities for the clinical outcome of medical management compared to surgery. This point has been added in the study limitation with further details.

Revised manuscript (Discussion): Firstly, the prognostic implications of the discordance between AVACT and AVAecho could not be addressed in this study. This resulted from the discordant results between CT and echocardiography not being considered when determining the timing of AVR. Furthermore, as echocardiography was the standard exam, the effect of discrepancies between two modalities on the patients outcome could not be evaluated. Secondly, our cohort was limited to patients who underwent AVR and therefore does not evaluate the effect on mortality due to the natural course of disease according to AS severity. As our study included patients with only a narrow higher end (severe) of AS, as opposed to the lower end (mild) of AS, this can cause selection bias. Future studies focusing on assessing the modality of choice to establish the optimal time of surgery and the effect of AS severity grading using these different modalities would be of value in order to determine the clinical outcome of medical management compared to surgery.

E-9. Have a paragraph before limitations in the discussion called clinical implications. What are the main implications for your study? When and how do you recommend CT-AVA be used and what thresholds for severe? How does your study change current management?

Response: The aim of this study was to demonstrate the factors affecting AVA discrepancies measured on echocardiography and CT. Patients with AS who underwent pre-operative echocardiography and CT for aortic valve replacement were evaluated. Of the patients analysed, ~11% of those with severe AS based on echocardiography showed discordant grading of severe AS between echocardiography and CT. Patients with larger BSA, AVAecho, tricuspid valve morphology, and annulus area normalized to the BSA were significant factors that were associated with discordant grading of AVA. The combined use of CT and echocardiography in severe AS patients should be emphasized and might be helpful for AS grading. A recent study demonstrated that surgical intervention could improve survival even among asymptomatic patients with severe AS [4]. Therefore, the decision to perform surgery in an asymptomatic patient further highlights the accurate stratification of severity of AS in those patients.

Reference

4. Kang DH, Park SJ, Lee SA, Lee S, Kim DH, Kim HK, et al. Early Surgery or

Conservative Care for Asymptomatic Aortic Stenosis. The New England journal of

medicine. 2020;382(2):111-9.

E-10. Any items you can’t address above need to add to limitations.

Response: Thank you for your valuable comment which was made to help improve our paper. We have revised the manuscript as described above.

Comments from Reviewer #1

1-Retrospective study.

2-Data collected from medical records

R1-1. 3-Methods section lacks details on how the AVA by CT was calculated. Did the authors used the CT maximal LVOT diameter, average area or planimetered LVOT area?

Response: Thank you for your comment. In response, we have added an additional description for the AVACT in our revised manuscript. AVACT was calculated by using the LVOT area measured on CT in the continuity equation with VTI at LVOT and transaortic flow on echocardiography (a hybrid of measures from both CT and echocardiography; AVACT = LVOTCT × VTILVOT/VTIAo). The LVOT area was determined by πr2 using a circular LVOT area , in which an average was used for the diameter.

Revised manuscript (Methods): AVACT was calculated by using the LVOT area measured on CT (LVOT area approximated by πr2 with average diameter used for r) in the continuity equation with VTI at LVOT and transaortic flow on echocardiography (a hybrid of measures from both CT and echocardiography; AVACT = LVOTCT × VTILVOT/VTIAo).

R1-2. 4-Discordant valve area was defined when the difference between echo and CT was>0.2cm2. This occurred in a relatively small number of patients.

Response: We used a 1.2 cm2 cut-off for diagnosing severe AS on CT and a 1.0 cm2 cut-off for echocardiography in accord with the previous literature (Reference 13). These cut-off values are also widely used and accepted by most clinicians and researchers. The discordant grading for severe AS occurred in 10.96% (56/511) of patients with severe AS. This is because the two modalities (CT and echocardiography) are well correlated to measure the AVA; however, a value of ~10% as a total of severe AS patients is not small or a trivial matter and do not deserve to be neglected in clinical practice. Moreover, although the number of patients were small according to these criteria, it was meaningful to evaluate the clinical characteristics of patients with discordant severity grading between two modalities for AVA.

Reference

13. Clavel MA, Malouf J, Messika-Zeitoun D, Araoz PA, Michelena HI, Enriquez-

Sarano M. Aortic valve area calculation in aortic stenosis by CT and Doppler

echocardiography. JACC Cardiovasc Imaging. 2015;8(3):248-57.

R1-3. 5-As in prior studies AV by CT was largen than echo AVA.

Response: Yes, our results was consistent with previous studies (reference 13), in that AVACT was greater than AVAEcho.

Reference

13. Clavel MA, Malouf J, Messika-Zeitoun D, Araoz PA, Michelena HI, Enriquez-

Sarano M. Aortic valve area calculation in aortic stenosis by CT and Doppler

echocardiography. JACC Cardiovasc Imaging. 2015;8(3):248-57.

R1-4. 6-The main objective of the study was to find the determinants form discrepant AVA

Response: Yes, correct. The main aim of this study was to find and demonstrate the factors affecting AVA discrepancies measured on CT and echocardiography.

R1-5. 7-In the bland Altman plot shown, the X axis shows the echo AVA and not the average of Echo and CT as is typically done.

Response: We agree that typically, the average of both measures is used in a Bland-Altman plot and we can also change the X axis to plot the average of the echo and CT data. However, as demonstrated in response to E-6, we wanted to demonstrate the absolute value of echocardiography rather than the mean of measures using two modalities to be more exact. We have now revised the Bland-Altman plot with the average of the echo and CT as the X-axis value below for Figure 3. However, the value of ICC does not appear to change.

Revised manuscript (Figure 3): Bland-Altman plot of AVAecho and AVACT (X-axis shows a mean of measures from echocardiography and CT).

R1-6. 8-Not clear what the unique contribution to this paper compared to similar ones that already exist in the literature.

Response: There were several previous studies that compared the AVAecho and AVACT; however, there was no demonstration that certain patient factors can affect the discrepancy between two measures. Although currently echocardiography plays the primary role in evaluating AVA prior to make a decision for AVR or TAVI, measurements using echocardiography can be inaccurate in certain cases. In such cases, CT can also provide anatomical information as a complementary tool. Moreover, when evaluating AVA in patients with low-flow/low-gradient AS, there can be discordant results based on two modalities for grouping the patients to either true severe AS or not. Thus, it is imperative to understand the differences as well as the pitfalls of the two modalities and which patient factors can result in the discordant grading for AS based on the two modalities in clinical practice.

Comments from Reviewer #2

The manuscript entitled "Differences in Aortic Valve Area Measured on Cardiac CT and Echocardiography in Patients with Aortic Stenosis" by Koo. et al. aimed to compare the aortic valve area AVA measured on CT and echocardiography, and demonstrate the factors that lead to discordant AVA readings between CT and echocardiography. From the 781 retrospectively selected patients, 95.51% were documented to have echocardiographic severe aortic stenosis and 10.96% of those had discordance between AVAecho and AVACT. Larger BSA, AVAecho, tricuspid AV morphology and indexed annulus area were associated with AVA discordance between echo and CT.

The authors have done a lot of work in collating this information and improving our knowledge in multimodality AS classification with few clarifications requested.

R2-1. It should be highlighted in the text that the main comparison between AVAecho and AVACT utilizes continuity equation for both and thus are comparisons of an echo solely or a hybrid approach. This said, a hybrid approach measurement can also be simplified to the comparison of annular area in both modalities.

Response: Thank you for your comment. We also agree and we tried to clarify those points in the revised manuscript, both the Abstract and Methods section. AVA on echocardiography was calculated using a continuity equation with VTI. We added an additional description for the AVAecho and AVACT in our revised manuscript. AVACT was also calculated by using a hybrid method incorporating information from both echocardiography and CT, with the LVOT area measured on CT in the continuity equation with VTI at LVOT and transaortic flow on echocardiography (AVACT = LVOTCT × VTILVOT/VTIAo). For the LVOT area, a circular LVOT area was estimated by πr2 using an average diameter.

Revised manuscript (Abstract): AVA was obtained by AVA on echocardiography (AVAecho) and CT (AVACT) using a measurement of the left ventricular outflow tract on each modalities and correlations between those measures were evaluated.

Revised manuscript (Methods):

The maximal and mean pressure gradients (PG) across the AV were estimated using a modified Bernoulli equation, and the AVA was calculated from the continuity equation with VTI (AVAecho). [ÿ]

AVACT was calculated by using the LVOT area measured on CT (LVOT area approximated by πr2 with the average diameter used for r) in the continuity equation with VTI at LVOT and transaortic flow on echocardiography (a hybrid of measures from both CT and echocardiography; AVACT = LVOTCT × VTILVOT/VTIAo).

R2-2. Furthermore, the discussion section sheds less light on AVAplani as a comparison and thus is confusing as the norm of a CT approach is usually to check planimetry area measurements. If that is not the case, it is then important to emphasize the differences within CT measurements whether measurement have been taken by the hybrid approach or by planimetry.

Response: Thank you for your valuable comment. Accurately measuring AVA using a planimetry approach is limited due to the difficulty in drawing the maximal systolic opening area on 2D-thin slice thickness images as the tips of the aortic cusps are not contained to one 2D plane. On the other hand, using thick slice thickness images for planimetry area measurements makes it challenging to outline the margin of cusps due to the blurring of images which can lead to overestimating the valve opening area. Therefore, calculating AVA by incorporating velocity information from echocardiography and the size of LVOT on high spatial resolution cardiac CT images based on continuity equations can be more accurate to reflect the maximal systolic opening of AV. We further discuss this point in the Discussion section as shown below.

Revised manuscript (Discussion): In this study, the correlation between AVAecho and AVACT showed a high positive correlation, whereas the correlation between AVAplani and AVAecho was moderate (r, 0.79 vs. 0.52). As a result of this finding, we further defined discordant and concordant groups based on AVACT by the continuity equation rather than AVAplani. Accurately measuring AVA using a planimetry approach is limited due to the difficulty in drawing the maximal systolic opening area on 2D-thin slice thickness images as the tips of the aortic cusps are not contained to one 2D plane. On the other hand, using thick slice thickness images for planimetry area measurements makes it challenging to outline the margin of cusps due to the blurring of images which can lead to overestimating the valve opening area. Therefore, calculating AVA by incorporating velocity information from echocardiography and the size of LVOT on high spatial resolution cardiac CT images based on continuity equations can be more accurate to reflect the maximal systolic opening of AV.

- End -

Submitted filename: Response letter 20221121.docx

 10.1371/journal.pone.0280530.r003 Decision Letter 1 Wang Tom Kai Ming Academic Editor 2023 Tom Kai Ming Wang This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 1

2 Jan 2023

Differences in Aortic Valve Area Measured on Cardiac CT and Echocardiography in Patients with Aortic Stenosis

PONE-D-22-24629R1

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Reviewers' comments:

 10.1371/journal.pone.0280530.r004 Acceptance letter Wang Tom Kai Ming Academic Editor 2023 Tom Kai Ming Wang This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

10 Jan 2023

PONE-D-22-24629R1

Differences in Aortic Valve Area Measured on Cardiac CT and Echocardiography in Patients with Aortic Stenosis

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