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Rupture risk parameters upon biomechanical analysis independently change from vessel geometry during abdominal aortic aneurysm growth

Open AccessPublished:November 19, 2022DOI:https://doi.org/10.1016/j.jvssci.2022.10.004

      Article highlights

      • Type of Research: Modeling study
      • Key Findings: 32 AAA patients with consecutive CT-angiographies were semi-automatically segmented for geometrical and biomechanical analysis to identify peak wall stress (PWS) and rupture index (PWRI). A linear transformation was used to predict maximum stress and luminal thrombus (ILT) points during AAA growth and measured their relative position change over the vessel wall.
      • Take home Message: The change of positions of maximum ILT thickness, PWS and PWRI is independent from most geometric aneurysm measurements during individual aneurysm growth and could thus be relevant for patient-specific rupture risk estimation.

      Abstract

      Objective

      The indication for abdominal aortic aneurysm repair (AAA) is based on a diameter threshold. However, mechanical properties, such as peak wall stress (PWS) and peak wall rupture index (PWRI), influence the individual rupture risk. This study aims to correlate biomechanical and geometrical AAA characteristics during aneurysm growth applying a new linear transformation-based comparison of sequential imaging.

      Patients and Methods

      AAA Patients with two sequential CT-angiographies (CTA) were identified from a single-center aortic database. Patient characteristics included age, genderand co-morbidities. Semi-automated segmentation of CTAs was performed using Endosize© (Therenva) for geometric variables (diameter, neck configuration, α/β angle, vessel tortuosity) and for finite element method (FEM) A4 Clinics© Research Edition (Vascops) for additional variables (intraluminal thrombus (ILT), vessel volume, PWS, PWRI). Maximum point coordinates from CT 1 were predicted for CT 2 using linear transformation along fix and validation points to estimate spatial motion. T-test and Pearson’s correlation were used for comparison.

      Results

      32 eligible patients (median age 70 years; were included. The annual AAA growth rate was 3.7mm (2.25-5.44, p<0.001) between CTs. AAA (+17%, p<0.001) and ILT (+43%. p<0.001) volume, maximum ILT thickness (+35%. p<0.001), ß angle (+1.96°, p=0.017) and iliac tortuosity (+0.009, p=0.012) increased significantly. . PWS (+12%, p= 0.0029) and PWRI (+16%. p<0.001) differed significantly between both CTAs.
      Both mechanical parameters correlated most significantly with the AAA volume increase (r: 0.68, p<0.001 and r=0.6, p<0.001). Changes in PWS correlated best with the aneurysm neck configuration. The spatial motion of maximum ILT thickness was 14.4mm (7.3-37.2), for PWS 8.4mm (3.8-17.3) and 11.5mm (5.9-31.9) for PWRI. Here, no significant correlation with any of the aforementioned parameters, nor patient age, nor time interval between CTs were observed.

      Conclusion

      PWS correlates highly significant with vessel volume and aneurysm neck configuration. Spatial motion of maximum ILT thickness, PWS and PWRI is detectable and predictable – and might expose different aneurysm wall segments to maximum stress throughout aneurysm growth. Linear transformation could thus add to patient-specific rupture risk analysis.

      Keywords

      Introduction

      Abdominal aortic aneurysm (AAA) is the most frequent aneurysm disease with the inherent threat of rupture
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      Screening for abdominal aortic aneurysm.
      . Despite very good clinical and patient-related outcomes for elective open or, most frequently, endovascular aortic repair (EVAR), rupture is still associated with a considerable mortality and postoperative morbidity
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      Indication for elective aortic repair is based mostly on reaching a maximum transverse diameter threshold of 50-55 mm
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      • et al.
      The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm.
      . Additionally, fast growth, local symptoms and eccentric configuration do influence clinical decision-making. However, approx. 1-2% of AAAs below the diameter threshold rupture, whereas some huge aneurysms remain intact over a patient’s lifetime
      • Brown L.C.
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      Abdominal aortic aneurysm expansion: risk factors and time intervals for surveillance.
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      The aneurysm wall and the underlying intraluminal thrombus (ILT) form a complex biological compartment characterized by cytokine production and i.e. accumulation of neutrophil extracellular traps (NETs)
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      .This might in parts account for constant aortic remodeling throughout AAA growth along with pathomechanisms inherent to the aneurysm wall
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      • Katsargyris A.
      • Kuivaniemi H.
      • Defraigne J.O.
      • Nchimi A.
      • et al.
      Abdominal aortic aneurysms.
      ,
      • Gasser T.C.
      • Miller C.
      • Polzer S.
      • Roy J.
      A quarter of a century biomechanical rupture risk assessment of abdominal aortic aneurysms. Achievements, clinical relevance, and ongoing developments.
      . Semi-automatic post-processing of CT-angiograms (CTA), such as through the finite element method (FEM) has been proposed to study the rupture risk of individual patients. The aneurysm is thought to rupture once the mechanical stress in the vessel wall exceeds the aortic wall strength
      • Gasser T.C.
      • Miller C.
      • Polzer S.
      • Roy J.
      A quarter of a century biomechanical rupture risk assessment of abdominal aortic aneurysms. Achievements, clinical relevance, and ongoing developments.
      ,
      • Singh T.P.
      • Moxon J.V.
      • Gasser T.C.
      • Golledge J.
      Systematic Review and Meta-Analysis of Peak Wall Stress and Peak Wall Rupture Index in Ruptured and Asymptomatic Intact Abdominal Aortic Aneurysms.
      . Therefore, either the calculated peak wall stress (PWS) itself, or the maximum between wall stress and an estimated local wall strength, a ratio known as peak wall rupture index (PWRI), serve as rupture risk factors. Additionally, other morphologic AAA characteristics, such as vessel volume, ILT, diameter or vessel length can be easily and reliably calculated based on segmentation of patients’ CTA
      • Trenner M.
      • Radu O.
      • Zschapitz D.
      • Bohmann B.
      • Biro G.
      • Eckstein H.H.
      • et al.
      Can We Still Teach Open Repair of Abdominal Aortic Aneurysm in The Endovascular Era? Single-Center Analysis on The Evolution of Procedural Characteristics Over 15 Years.
      . Yet, the timely evolution of biomechanical and morphological properties along with aneurysm growth is largely unclear, and their association with eventual rupture remains unknown
      • Singh T.P.
      • Moxon J.V.
      • Gasser T.C.
      • Golledge J.
      Systematic Review and Meta-Analysis of Peak Wall Stress and Peak Wall Rupture Index in Ruptured and Asymptomatic Intact Abdominal Aortic Aneurysms.
      ,
      • Lindquist Liljeqvist M.
      • Bogdanovic M.
      • Siika A.
      • Gasser T.C.
      • Hultgren R.
      • Roy J.
      Geometric and biomechanical modeling aided by machine learning improves the prediction of growth and rupture of small abdominal aortic aneurysms.
      .
      We hypothesized that AAA growth based on diameter enlargement between two consecutive CTAs is accompanied with significant changes in biomechanical and geometrical characteristics. Additionally, we hypothesized that parameters such as PWRI, PWS and ILT do not simply monotonously grow with aneurysm diameter and that their respective position also changes with AAA growth. We therefore introduce for the first time a linear transformation-based comparison of the respective maximum point positions towards the in-depth study of AAA growth dynamics.

      Patients and Methods

      Patient identification, inclusion criteria and data acquisition

      Patients were retrospectively identified from our aortic database (January 1, 2005 to December 31, 2019; Suppl. Fig. 1). All patients were operated on the infra-or juxtarenal aorta (cut-off >10mm neck length) for AAA by open surgical means during this time
      • Wanhainen A.
      • Verzini F.
      • Van Herzeele I.
      • Allaire E.
      • Bown M.
      • Cohnert T.
      • et al.
      Editor's Choice - European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Artery Aneurysms.
      ,
      • Trenner M.
      • Radu O.
      • Zschapitz D.
      • Bohmann B.
      • Biro G.
      • Eckstein H.H.
      • et al.
      Can We Still Teach Open Repair of Abdominal Aortic Aneurysm in The Endovascular Era? Single-Center Analysis on The Evolution of Procedural Characteristics Over 15 Years.
      .
      Patient data was anonymized for further analysis. The study was performed in accordance with the declaration of Helsinki and approved by the local ethics committee (Ethikkommission Klinikum rechts der Isar: 576/18 S).
      We included all patients who had at least one CTA (CT 1) 6-24 months prior to their final preoperative CTA (CT 2).
      Patients with post-dissection aneurysms or connective tissue disease were excluded. Also, patients with inadequate CTA data (≥2.5mm slice thickness; unsuccessful segmentation in VASCOPS© or Endosize©, see below) were excluded. Due to the low number of ruptured AAA cases meeting the inclusion criteria (N=2, data not shown), ruptures were also excluded.
      Data were obtained retrospectively from the department’s aortic database. Patient demographics and comorbidities (age, gender, arterial hypertension, smoking status, peripheral arterial disease, coronary artery disease, hyperlipidemia, diabetes mellitus, chronic obstructive pulmonary disease, renal insufficiency, and obesity) were retrieved from electronic patient records and outpatient follow-up examinations.

      Geometric AAA Analysis

      The morphologic analysis was performed semi-automatically with Endosize© (Therenva), a software for clinical assessment of AAAs as well as for EVAR planning (https://www.therenva.com/endosize) as previously described and validated by us and others
      • Trenner M.
      • Radu O.
      • Zschapitz D.
      • Bohmann B.
      • Biro G.
      • Eckstein H.H.
      • et al.
      Can We Still Teach Open Repair of Abdominal Aortic Aneurysm in The Endovascular Era? Single-Center Analysis on The Evolution of Procedural Characteristics Over 15 Years.
      ,
      • Kaladji A.
      • Cardon A.
      • Abouliatim I.
      • Campillo-Gimenez B.
      • Heautot J.F.
      • Verhoye J.P.
      Preoperative predictive factors of aneurysmal regression using the reporting standards for endovascular aortic aneurysm repair.
      ,
      • Kaladji A.
      • Lucas A.
      • Kervio G.
      • Haigron P.
      • Cardon A.
      Sizing for endovascular aneurysm repair: clinical evaluation of a new automated three-dimensional software.
      . Briefly, defined setpoints were manually entered in the segmented CTA (all non-ECG-gated). Then, a centerline was calculated and verified with eventual manual adjustment. Calculated parameters included: suprarenal to infrarenal neck angulation (α), infrarenal neck to AAA angulation (β), maximum transverse diameter, neck length, proximal and distal neck diameter (lowest renal artery to the beginning of the aneurysm) and aortic/iliac tortuosity index (centerline to direct “raceline” distance ratio: lowest renal artery to aortic bifurcation/aortic bifurcation to inguinal ligament)
      • Bryce Y.
      • Rogoff P.
      • Romanelli D.
      • Reichle R.
      Endovascular repair of abdominal aortic aneurysms: vascular anatomy, device selection, procedure, and procedure-specific complications.
      .
      Additionally, the maximum AAA diameter was calculated and verified by “classic means” with outer edge transversal measurement of the maximum diameter in a 3D multiplanar reconstruction.

      Biomechanic AAA Analysis

      A semi-automated biomechanics FEM analysis was performed using A4clinics Research Edition (Vascops GmbH) as described before
      • Gasser T.C.
      • Miller C.
      • Polzer S.
      • Roy J.
      A quarter of a century biomechanical rupture risk assessment of abdominal aortic aneurysms. Achievements, clinical relevance, and ongoing developments.
      ,
      • Lindquist Liljeqvist M.
      • Bogdanovic M.
      • Siika A.
      • Gasser T.C.
      • Hultgren R.
      • Roy J.
      Geometric and biomechanical modeling aided by machine learning improves the prediction of growth and rupture of small abdominal aortic aneurysms.
      . Briefly, a 3D model of the AAA is semi-automatically segmented from CTA images, identifying lumen, ILT and the outer contour of the vessel wall. The segmentation covers the aortic segment between the lowest renal artery and the aortic bifurcation, and the investigator manually corrects the model in line with the instructions for use, i.e. given the segmentation mismatch exceeds 2mm. A standardized arterial pressure of 140/80 mmHg was used for all FEM computations, and model output are the total vessel volume, maximal luminal diameter, lumen volume, maximal ILT thickness, ILT volume, mean ILT stress, PWS and PWRI. The PWS represents the maximal stress, whilst PWRI is the maximum ratio between wall stress and wall strength in the aneurysm.

      Linear transformation Analysis

      Given the coordinates (x, y, z) of the points of maximum ILT thickness, PWS and PWRI in CT 1, linear transformation (also known as rigid registration or affine transformation) was used to predict said points in CT 2. Minimizing the error through least square optimization of the x, y and z coordinates of up to nine corresponding points (left/right renal artery, superior mesenteric artery, aortic bifurcation, proximal left/right common iliac arteries and 1-3 lumbar arteries if available) in CT 1 and CT 2 determined the transformation matrix (MATHEMATICA 12.0, Wolfram). An additional point (i.e. calcified plaque or inferior mesenteric artery) clearly visible in both CTAs validated the transformation matrix. The applied linear transformation was considered successful, if the distance between predicted position and the actual position of the validation point in CT 2 was below 15 mm.
      All measurements, including biomechanical parameters and the linear transformation, were performed by an experienced analyzer (DZ) and reviewed by an experienced vascular surgeon/analyzer (AB, TCG). Upon discrepant results, all three investigators performed joint analysis.

      Statistics and Figure composition

      Patients and AAA characteristics are shown as median with interquartile range (IQR) for continuous variables and absolute numbers with percentages for categorical data.
      Given the small number of patients, a Wilcoxon test was used to test for significant changes between CT1 and CT2 as well as between the different groups. It considers different variances across the compared groups and minimizes the possible influence of outliers. Pearson correlation coefficient (r) tested the linear correlations between different variables, and the level of significance was set at p < 0.05. All statistical analyses were performed using R version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria. https://www.r-project.org/) and graphics were created using the ggplot2 package.

      Results

      In total, 32 patients met the inclusion criteria and were included in the study (Suppl. Fig. 1). Thirty patients were male (median age 70 years; IQR: 62-75). Detailed patient characteristics including co-morbidities are listed in Table 1. Two patients had symptomatic AAA before operation and seven patients had additional iliac aneurysms.
      Table 1Patients’ and aneurysm characteristics. (COPD = chronic obstructive pulmonary disease; PAOD = peripheral arterial occlusive disease; symptomatic AAA: 2x abdominal pain w/o other cause; infra- vs. juxtarenal AAA: >10mm neck length; plus iliac aneurysm: 2x bilateral; ASS = aspirin, ACE = angiotensin converting enzyme)
      Patients’ characteristics (N=32)
      Age @ operation (y, median, IQR)70 [62 - 75]
      Male sexn (%)30 (94)
      Comorbiditiesn (%)
       Hypertension26 (81)
       Diabetes9 (28)
       Hyperlipidemia24 (75)
       Heart disease13 (41)
       COPD7 (22)
       PAOD5 (16)
      Smoking Status
       Current20 (63)
       Ex7 (22)
       Never3 (9)
      Medication
       ASA/Clopidogrel20 (63)
       ACE inhibitors10 (31)
       Statins18 (56)
       Metformin2 (6)
       Insulin1 (3)
      elevated/reduced serum parameters
      C-reactive protein(≥ 0.5 mg/dl)8 (44)
      Leukocytes(< 3.5 / > 9.5 x 10³/μl)3 (9)
      Thrombocytes(< 80 / > 350 x 10³/μl)1 (3)
      Creatinine(> 1.2 mg/dl)5 (16)
      AAA characteristics
      asymptomatic (vs. symptomatic)30 (94)
      Localizationn (%)
      infrarenal (vs. juxtarenal)19 (59)
      plus iliac7 (22)
      Time difference between the two analyzed CTAs was 14 (9-24) months (Table 2), within which the AAA diameter increased significantly by 3.7 (2.25-5.44) mm/year (absolute values: 50mm (45.8-52.0; CT 1) to 55mm (52.0-56.8; CT 2), p<0.001). Upon morphologic analysis, only the ß angle (+1.96°, p=0.017) and the iliac tortuosity index (+0.009, p=0.012) changed significantly, whereas all other parameters showed only slight alterations (Fig. 1A/Table 2). On the other hand, the volumes of the entire aneurysm (+17%, p<0.001) and the ILT (+43%. p<0.001), as well as the maximum ILT thickness (+35%. p<0.001) increased significantly. Also, the changes of PWS (+12%, p= 0.0029) and PWRI (+16%. p<0.001) were significant from CT 1 to CT 2 (Fig. 1B/Table 2).
      Table 2Sequential Endosize© and Vascops© CT analysis data. (values are displayed as median and interquartile range: IQR; p<0.05 is considered significant and highlighted bold upon Wilcoxon rank sum test; CIA=common iliac artery)
      (median, IQR)CT 1CT 2Δ (absolute)Δ (%)p (Wilcoxon)normalized

      per 12 months
      time (months)14 [9-24]
      AAA diameter (mm)49.9 [45.8 - 52.0]55.0 [52.0 - 56.8]5.4 [3.1 - 7.4]11 [6 - 16]0.00000183.70 [2.25 - 5.44]
      α angle (°)14.8 [10.9 - 20.7]18.2 [10.8 - 24.7]0.5 [-1.5 - 6.2]2.4 [-13.0 - 48.0]0.230.38 [-0.98 - 2.82]
      β angle (°)28.7 [21.5 - 33.7]30.3 [22.6 - 40.0]2.9 [-1.8 - 5.9]10 [-4 - 18]0.0171.96 [-0.98 - 3.17]
      neck length (mm)20.5 [9.0 - 37.5]20.0 [7.0 - 41.8]-0.5 [-4.5 - 3.8]-1 [-23 - 20]0.79-0.20 [-3.71 - 1.60]
      neck diameter (mm)24 [22.0 - 27.6823.9 [22.6 - 26.0]-0.9 [-1.8 - 1.0]-4 [-8 - 4]0.13-0.41 [-1.25 - 0.54]
      CIA length left61 [45 - 76]57 [49 - 69]-2 [-10 - 4]-4 [-16 - 8]0.065-1.72 [-7.03 - 2.42]
      CIA length right59 [40 - 69]54 [42 - 69]-2 [-5 - 3]-3 [-10 - 5]0.22-0.60 [-5.14 - 2.68]
      aortic tortuosity index1.07 [1.06 - 1.12]1.08 [1.06 - 1.14]0.002 [-0.006 - 0.022]0.2 [-0.4 - 2.1]0.220.002 [-0.004 - 0.012]
      iliac tortuosity index1.30 [1.21 - 1.36]1.30 [1.23 - 1.38]0.016 [-0.012 - 0.045]1.3 [-1.0 - 3.5]0.0120.009 [-0.017 - 0.026]
      max. lumen diameter (mm)37.0 [32.4 - 41.6]39.5 [34.9 - 46.5]3.9 [1.1 - 7.1]13 [4 - 20]0.0000323.26 [0.93 - 4.67]
      max. ILT thickness (mm)14.0 [9.0 - 20.0]17.7 [14.9 - 27.0]4.8 [1.1 - 7.2]35 [5 - 61]0.0000323.04 [1.36 - 4.96]
      total lumen volume (mm3)68 [48 - 82]71 [54 - 95]8 [3 - 18]18 [4 - 40]0.000286.70 [1.85 - 11.50]
      total vessel volume (mm3)129 [93 - 164]150 [121 - 206]24 [18 - 45]17 [13 - 38]0.000001220.85 [14.77 - 30.70]
      total ILT volume (mm3)37 [26 - 64]63 [40 - 92]18 [7 - 32]43 [16 - 81]0.00004413.20 [5.56 - 25.66]
      PWS (kPa)190 [156 - 229]195 [178 - 257]24 [2 - 38]12 [1 - 23]0.002912.66 [1.41 - 26.65]
      PWRI0.36 [0.33 - 0.42]0.38 [0.31 - 0.53]0.05 [0.00 - 0.10]16 [0 - 24]0.000510.03 [0.00 - 0.07]
      Figure thumbnail gr1
      Figure 1Endosize© and Vascops© data acquisition. The pictures display an exemplary 3D CTA reconstruction after successful semi-automated segmentation. (A) Using Endosize©, the neck diameter and length as well as α and β angulations are calculated. The maximum AAA diameter (Dmax) is calculated perpendicular to the center line (red dotted line). The aortic/iliac tortuosity indeces are calculated as the ratio centerline/raceline (black dotted arrow) between P2 (lowest renal artery)/P4 (aortic bifurcation) and P4/P8 (inguinal ligament), respectively. (B) Using Vascops© A4 Clinics Research, the finite element method captures areas (displayed as heatmap) and maximum points of intraluminal thrombus (ILT, mm) thickness, peak wall stress (PWS; v. Mises stress, kPa) and peak wall rupture index (PWRI; rupture risk index). (Orientation of reconstruction represented by anterior (A), posterior (P), left (L) and right (R))
      These changes in PWS and PWRI correlated most significantly with the total AAA volume increase (PWS: correlation co-efficient r: 0.68, p<0.001; PWRI: r=0.6, p<0.001) (Suppl. Fig. 2; Table 3). Only the difference in PWRI showed a weak correlation with aneurysm diameter increase (r=0.39, p=0.026) (Suppl. Fig. 3). Changes in PWS correlated best with the configuration of the aneurysm neck. Additionally, a weak correlation with patient age was noted (r=0.45, p=0.010). Naturally, most values correlated well with the time interval between CTs (Table 2/ Suppl. Table I).
      Table 3Correlation analysis of absolute PWS and PWRI changes with age, geometric and volumetric AAA changes. (absolute values are correlated; p<0.05 is considered significant and highlighted bold; examples of correlation plots are displayed in Suppl. Fig. 2/3)
      Pearson correlationΔ (abs) PWSΔ (abs) PWRI
      rprp
      Δ age @ operation0.450.00970.240.20
      Δ (abs) AAA diameter0.250.170.390.026
      Δ (abs) α angle0.380.030.180.32
      Δ (abs) β angle0.400.0230.250.17
      Δ (abs) neck length0.460.00760.120.51
      Δ (abs) neck diameter0.0950.610.120.51
      Δ (abs) CIA length left-0.0150.930.0910.62
      Δ (abs) CIA length right0.00610.970.110.57
      Δ (abs) aortic tortuosity index0.190.310.220.23
      Δ (abs) iliac tortuosity index0.210.240.120.51
      Δ (abs) max. lumen diameter0.610.000210.470.0063
      Δ (abs) max. ILT thickness0.300.0920.300.1
      Δ (abs) total lumen volume0.640.000070.450.01
      Δ (abs) total vessel volume0.680.0000180.600.00032
      Δ (abs) total ILT volume0.250.160.330.062
      For additional analysis, the spatial motion of the point at which maximum ILT thickness, PWS and PWRI appeared, was monitored. To this end, said points were projected from CT 1 to CT 2 using the aforementioned linear transformation, enabling to measure the distance to the positions, where maximum ILT thickness, PWS and PWRI actually appeared in CT 2 (Fig. 2/Suppl. Fig. 4). These distances were 14.4mm (7.3-37.2) for maximum ILT, 8.4mm (3.8-17.3) for maximum PWS and 11.5mm (5.9-31.9) for maximum PWRI. The distance between the predicted and the literal position of the validation point was 7.9mm (5.3-10.9) (data not shown). However, no significant correlations of these motions with any of the morphological or biomechanical parameters, nor patient age, nor time interval of CTAs were observed (Table 4). Additionally, rank sum tests for differences between patients with large and small motions between the three maximum points did not reveal any significant differences in those groups (Suppl. Fig. 5A/Suppl. Table II). Annual AAA growth rate and total volume growth rate were equally distributed and thus not further analyzed in groups (Suppl. Fig. 5B).
      Figure thumbnail gr2
      Figure 2Linear transformation and maximum point motion assessment for maximum ILT thickness and PWS. Using Vascops©, several fixpoints, close to, but not within the actual aneurysm were defined and the x, y, z coordinates extracted (i.e. aortic bifurcation, superior mesenteric, renal, lumbar and iliac arteries: grey X). These defined the matrix for linear transformation and prediction of the validation point (i.e. inferior mesenteric artery: orange X) and the points of maximum ILT, PWS and PWRI (black/white dot, s. Suppl. Fig. 4 for PWRI). The distance between the actual and the predicted validation point in CT 2 was supposed to be <15mm for study inclusion. Then the distances between actual and predicted maximum points were calculated. (Orientation of reconstruction represented by anterior (A), posterior (P), left (L) and right (R))
      Table 4Correlation of maximum ILT thickness, PWS and PWRI spatial distance changes with geometric, volumetric and biomechanical parameters. (absolute values are correlated; p<0.05 is considered significant and highlighted bold)
      Pearson correlationDistance max ILTdistance PWRIdistance PWS
      rprprp
      Δ (abs) age @ operation-0.150.41-0.08230.660.08060.66
      Δ (abs) AAA diameter0.150.410.2050.260.05710.76
      Δ (abs) α angle-0.350.0530.06790.710.2150.24
      Δ (abs) β angle-0.0700.700.1860.310.1880.30
      Δ (abs) neck length-0.0750.680.1040.570.1550.4
      Δ (abs) neck diameter-0.260.15-0.04680.80-0.2060.27
      Δ (abs) aortic tortuosity index0.340.0580.1440.430.3190.075
      Δ (abs) iliac tortuosity index-0.0430.810.03090.870.2340.2
      Δ (abs) max. lumen diameter0.0860.640.1480.420.1100.55
      Δ (abs) max. ILT thickness0.180.32-0.3300.065-0.06590.72
      Δ (abs) total lumen volume-0.0620.740.1130.540.1100.55
      Δ (abs) total vessel volume0.0200.91-0.1540.40-0.1430.43
      Δ (abs) total ILT volume0.170.35-0.2080.25-0.2060.26
      Δ (abs) PWS0.0640.730.04210.82-0.1060.56
      Δ (abs) PWRI0.170.34-0.1240.5-0.01320.94

      Discussion

      To the best of our knowledge, this study explored for the first time the spatial motion of characteristic geometrical and biomechanical points of the aortic wall during AAA growth. A linear transformation has been used to explore said positions during consecutive aortic imaging. Our pilot study suggests that the motion of the point where extreme geometrical and biomechanical parameters have been identified is independent from other growth parameters, especially AAA diameter. Additionally, we demonstrate that an increase in maximum PWS and PWRI correlates highly significant with AAA volume and neck configuration.
      Between CT 1 and CT 2, aneurysm diameter changed significantly, along aneurysm volume and ILT characteristics (Table 2). AAA volume was demonstrated to grow independently and faster than diameter in the past
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      Combining Volumetric and Wall Shear Stress Analysis from CT to Assess Risk of Abdominal Aortic Aneurysm Progression.
      . Recent research suggests that volume growth, specifically the ratio between lumen and thrombus volume, might be a more sensitive parameter for eventual symptomatic state of disease or even rupture
      • Lindquist Liljeqvist M.
      • Bogdanovic M.
      • Siika A.
      • Gasser T.C.
      • Hultgren R.
      • Roy J.
      Geometric and biomechanical modeling aided by machine learning improves the prediction of growth and rupture of small abdominal aortic aneurysms.
      ,
      • Olson S.L.
      • Panthofer A.M.
      • Blackwelder W.
      • Terrin M.L.
      • Curci J.A.
      • Baxter B.T.
      • et al.
      Role of volume in small abdominal aortic aneurysm surveillance.
      ,
      • Joly F.
      • Soulez G.
      • Garcia D.
      • Lessard S.
      • Kauffmann C.
      Flow stagnation volume and abdominal aortic aneurysm growth: Insights from patient-specific computational flow dynamics of Lagrangian-coherent structures.
      . Therefore, AAA volume has even been included in medical intervention studies on AAA growth inhibition
      • Golledge J.
      • Pinchbeck J.
      • Tomee S.M.
      • Rowbotham S.E.
      • Singh T.P.
      • Moxon J.V.
      • et al.
      Efficacy of Telmisartan to Slow Growth of Small Abdominal Aortic Aneurysms: A Randomized Clinical Trial.
      . Accordingly, our results demonstrate a highly significant positive correlation of changes in PWS and PWRI with total vessel, luminal and ILT volume (Table 3, Suppl. Fig. 2, 3)
      • Lindquist Liljeqvist M.
      • Hultgren R.
      • Gasser T.C.
      • Roy J.
      Volume growth of abdominal aortic aneurysms correlates with baseline volume and increasing finite element analysis-derived rupture risk.
      .
      Especially, the rapid growth of ILT volume (43%) and thickness (35%) in comparison to AAA diameter (11%) might be an underestimated pathologic feature (Table 1)
      • Stevens R.R.F.
      • Grytsan A.
      • Biasetti J.
      • Roy J.
      • Lindquist Liljeqvist M.
      • Gasser T.C.
      Biomechanical changes during abdominal aortic aneurysm growth.
      . The ILT is considered not only as visco-elastic structural component with beneficial stress-buffering properties, but also as enzymatically active compartment producing cytokines and adding to the constant remodeling of the aortic wall
      • Sakalihasan N.
      • Michel J.B.
      • Katsargyris A.
      • Kuivaniemi H.
      • Defraigne J.O.
      • Nchimi A.
      • et al.
      Abdominal aortic aneurysms.
      ,
      • Gasser T.C.
      • Miller C.
      • Polzer S.
      • Roy J.
      A quarter of a century biomechanical rupture risk assessment of abdominal aortic aneurysms. Achievements, clinical relevance, and ongoing developments.
      ,
      • Boyd A.J.
      Intraluminal thrombus: Innocent bystander or factor in abdominal aortic aneurysm pathogenesis?.
      . Interestingly, the spatial motion of the point of the maximum ILT thickness, in comparison to the positions of maximum PWS and PWRI, was the most pronounced in our study (Fig. 2, Suppl. Table II). Additionally, patients with larger distances between predicted and the literal position of maximum ILT thickness showed a significantly increased PWRI (Suppl. Table II)
      • Horvat N.
      • Virag L.
      • Karsaj I.
      Mechanical role of intraluminal thrombus in aneurysm growth: A computational study.
      . A large motion of the point of the maximum ILT thickness during aneurysm growth, might therefore be linked to an increase in risk of rupture based on previous similar speculations.
      • Singh T.P.
      • Moxon J.V.
      • Gasser T.C.
      • Golledge J.
      Systematic Review and Meta-Analysis of Peak Wall Stress and Peak Wall Rupture Index in Ruptured and Asymptomatic Intact Abdominal Aortic Aneurysms.
      ,
      • Boyd A.J.
      Intraluminal thrombus: Innocent bystander or factor in abdominal aortic aneurysm pathogenesis?.
      ,
      • Throop A.
      • Bukac M.
      • Zakerzadeh R.
      Prediction of wall stress and oxygen flow in patient-specific abdominal aortic aneurysms: the role of intraluminal thrombus.
      AAA rupture is a local event in the aortic wall, and a large motion of the position of PWS or PWRI constantly exposes a “new” segment of the vessel wall to risk. To cope with that, the aneurysm wall remodels accordingly and previous histologic comparisons have demonstrated a distinct morphology in AAA wall samples with high vs. low PWRI
      • Erhart P.
      • Grond-Ginsbach C.
      • Hakimi M.
      • Lasitschka F.
      • Dihlmann S.
      • Bockler D.
      • et al.
      Finite element analysis of abdominal aortic aneurysms: predicted rupture risk correlates with aortic wall histology in individual patients.
      . However, histologic appearance is very heterogeneous among patient samples and the morphologic influence of ILT thickness is unclear
      • Rijbroek A.
      • Moll F.L.
      • von Dijk H.A.
      • Meijer R.
      • Jansen J.W.
      Inflammation of the abdominal aortic aneurysm wall.
      ,
      • Busch A.
      • Hartmann E.
      • Grimm C.
      • Ergun S.
      • Kickuth R.
      • Otto C.
      • et al.
      Heterogeneous histomorphology, yet homogeneous vascular smooth muscle cell dedifferentiation, characterize human aneurysm disease.
      . Thus, new imaging methods using radioactive or molecular magnetic resonance imaging probes are currently evaluated on a pre-clinical level to combine histologic features of remodeling with in vivo imaging approaches
      • Kaufmann J.O.
      • Brangsch J.
      • Kader A.
      • Saatz J.
      • Mangarova D.B.
      • Zacharias M.
      • et al.
      ADAMTS4-specific MR probe to assess aortic aneurysms in vivo using synthetic peptide libraries.
      • Gandhi R.
      • Cawthorne C.
      • Craggs L.J.L.
      • Wright J.D.
      • Domarkas J.
      • He P.
      • et al.
      Cell proliferation detected using [(18)F]FLT PET/CT as an early marker of abdominal aortic aneurysm.
      • Forsythe R.O.
      • Dweck M.R.
      • McBride O.M.B.
      • Vesey A.T.
      • Semple S.I.
      • Shah A.S.V.
      • et al.
      18)F-Sodium Fluoride Uptake in Abdominal Aortic Aneurysms: The SoFIA(3) Study.
      . Ideally, such data will be considered for future versions of FEM-based AAA biomechanics to integrate remodeling during aneurysm growth and increase the precision of the rupture risk assessment.
      This pilot study introduced a fundamentally new approach with several limitations, however. Only a small number of patients could be included in the study, mostly due to missing consecutive imaging (Suppl. Fig. 1). Thereof, the majority were male patients (94%, all Caucasian) with, however, unclear significance regarding sex and race disparities upon FEM analysis (Table 1).
      • Singh T.P.
      • Moxon J.V.
      • Gasser T.C.
      • Golledge J.
      Systematic Review and Meta-Analysis of Peak Wall Stress and Peak Wall Rupture Index in Ruptured and Asymptomatic Intact Abdominal Aortic Aneurysms.
      Considering the high heterogeneity among AAA patients, this might conceal possible errors during statistical analysis. Ideally, the method should be validated including patients with >2 CTAs. Semi-automated CTA segmentation with consecutive i.e. diameter calculation harbors the risk of false measurements, if not reviewed and manually corrected, where needed.
      Whilst several groups have demonstrated feasibility and applicability for different research purposes, morphologic and FEM analyses are technically demanding and the CTAs included are not standardized (i.e. no ECG-gating)
      • Trenner M.
      • Radu O.
      • Zschapitz D.
      • Bohmann B.
      • Biro G.
      • Eckstein H.H.
      • et al.
      Can We Still Teach Open Repair of Abdominal Aortic Aneurysm in The Endovascular Era? Single-Center Analysis on The Evolution of Procedural Characteristics Over 15 Years.
      ,
      • Lindquist Liljeqvist M.
      • Bogdanovic M.
      • Siika A.
      • Gasser T.C.
      • Hultgren R.
      • Roy J.
      Geometric and biomechanical modeling aided by machine learning improves the prediction of growth and rupture of small abdominal aortic aneurysms.
      ,
      • Kaladji A.
      • Lucas A.
      • Kervio G.
      • Haigron P.
      • Cardon A.
      Sizing for endovascular aneurysm repair: clinical evaluation of a new automated three-dimensional software.
      . In addition, using a patient-specific vs. standardized blood pressures, as done in our FEM-based biomechanical analysis, is a matter of current debate, probably also in the context of gender differences
      • Gasser T.C.
      • Miller C.
      • Polzer S.
      • Roy J.
      A quarter of a century biomechanical rupture risk assessment of abdominal aortic aneurysms. Achievements, clinical relevance, and ongoing developments.
      ,
      • Singh T.P.
      • Moxon J.V.
      • Gasser T.C.
      • Golledge J.
      Systematic Review and Meta-Analysis of Peak Wall Stress and Peak Wall Rupture Index in Ruptured and Asymptomatic Intact Abdominal Aortic Aneurysms.
      . However, in contrast to the values of PWS and PWRI, their position, and anyway the position of maximum ILT, is very insensitive to blood pressure.
      Hence, larger studies with more patients and possibly additional consecutive imaging with more than two time points are needed to better evaluate the method and results presented here. More crucially, analyses of ruptured AAA cases with consecutive preceding aortic imaging are scarce
      • Washington C.B.
      • Shum J.
      • Muluk S.C.
      • Finol E.A.
      The association of wall mechanics and morphology: a case study of abdominal aortic aneurysm growth.
      . Ultimately, studies with prospective patient analysis, are needed to compare the patient-individual rupture risk alongside standard diameter evaluation as current gold standard for preemptive AAA repair to gain future clinical perspective
      • Brown L.C.
      • Thompson S.G.
      • Greenhalgh R.M.
      • Powell J.T.
      • Participants U.K.S.A.T.
      Fit patients with small abdominal aortic aneurysms (AAAs) do not benefit from early intervention.
      .

      Conclusion

      Increased PWS correlated highly significantly with vessel volume and aneurysm neck configuration, whilst increased PWRI correlated with vessel volume and AAA diameter. In addition, the motion of the maximum ILT thickness, PWS and PWRI positions is independent from most geometric aneurysm measurements during aneurysm growth. It might therefore bear additional valuable information to assess AAA rupture risk, since there is a constant exposure of different aortic segments to differential PWS.

      Funding

      A one-year license of EndoSize® (Therenva) and A4clinics Research Edition (Vascops) was acquired for a different project funded by the German Heart Foundation (Dt. Herzstiftung) with a grant given to A Busch (F/46/18).

      Author Contributions

      DZ, BB, BL, TCG and AB have acquired and analyzed the data. LM, CR and HHE helped to interpret the data and to draft the manuscript. AB, LM and HHE have acquired the necessary funding. AB and TCG take overall responsibility. All authors have read, edited and approved the final version of the manuscript.

      Conflict of Interest

      Christian T Gasser is CEO of Vascops. All other authors have no conflict of interest.

      Acknowledgement

      Not applicable.

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      Linked Article

      • Biomechanical rupture risk prediction with AAA growth.
        JVS-Vascular Science
        • Preview
          Abdominal aortic aneurysms (AAA) are repaired when they meet diameter criteria, or when they become symptomatic or rupture. The use of aortic diameter as the primary criterion in the decision to repair fails address the considerable numbers of AAA which rupture below this operative threshold (1); particularly in women (2). Improved prediction of AAA behavior is required to prevent significant morbidity and mortality.
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