Aortic stiffness in adolescent Turner and Marfan syndrome patients

Aortic stiffness in adolescent Turner and Marfan syndrome patients Abstract OBJECTIVES Turner syndrome (TS) and Marfan syndrome (MFS) are partially characterized by aortopathies with a risk of developing severe aortic dilation, stiffness and consequent dissection and aneurysm formation. The incidence of a bicuspid aortic valve (BAV) is also increased in TS. We investigated aortic stiffness in teenage TS and MFS patients and evaluated to what degree stiffness in TS patients is augmented by the presence of a BAV. METHODS Fifty-seven patients with TS (n = 37) and MFS (n = 20), as well as 22 controls with similar age and size distribution underwent evaluation of thoracic aortic stiffness using phase-contrast magnetic resonance imaging. Calculated stiffness indices including pulse wave velocity (PWV), distensibility and relative area change (RAC) were collected to characterize the ascending aorta and descending aorta. PWV was also determined to evaluate global aortic arch stiffness. RESULTS Patients with TS had reduced distensibility (0.43 vs 0.58%/mmHg, P < 0.05) and RAC (21 vs 29%, P < 0.01) in the ascending aorta when compared with normal controls. Similarly, patients with MFS had reduced ascending aortic distensibility (0.39 vs 0.58%/mmHg, P < 0.05) and RAC (22 vs 29%, P < 0.05). There were no differences in measured PWV in the ascending aorta. Patients with TS had significantly elevated PWV measured in the aortic arch when compared with controls (2.7 vs 1.9 m/s, P < 0.05). Patients with MFS had more prominent elevation in aortic arch PWV (4.2 vs 1.9 m/s, P < 0.01). The descending aortas had decreased distensibility (0.36 vs 0.55%/mmHg, P < 0.05) and RAC (18 vs 25%, P < 0.01) only in MFS patients. Additionally, 18 TS patients with a BAV were compared with 19 TS patients with a trileaflet aortic valve, without significant differences observed in any of the considered stiffness indices. CONCLUSIONS TS and MFS teenage patients display evidence of increased aortic stiffness. In TS patients, this is focused in the ascending aorta and is independent of the presence of a BAV. MFS patients display a generalized reduction in compliance of the entire aorta. Marfan syndrome , Turner syndrome , Aorta , Stiffness INTRODUCTION Turner syndrome (TS) and Marfan syndrome (MFS) are genetic disorders in which altered connective tissue composition may lead to severe aortopathy and increased risk for aortic dilation and dissection [1, 2]. Both patient groups represent the younger spectrum of patients at risk for developing these complications [3, 4]. The accelerated risk of developing an acute aortic event in TS and MFS is primarily due to altered extracellular matrix composition in aortic media manifesting as elevated aortic stiffness which along with altered haemodynamic shear forces may lead to development of intimal tears or rapidly progressive aortic dilation [5–7]. Consequently, early and extensive surgical intervention may be advocated to avoid an acute aortic events [8, 9]. Better understanding of aortic biomechanical properties is warranted to identify disease-specific indicators to guide therapy. Computed tomography (CT) and magnetic resonance imaging (MRI) are standard imaging modalities used for baseline evaluation and serial monitoring of TS and MFS patients [10]. CT allows comprehensive anatomical characterization of the thoracic aorta and is preferentially used for preoperative planning [11]. MRI provides detailed evaluation of aortic wall motion allowing for segmental analysis of aortic stiffness and avoids patient exposure to ionizing radiation. Furthermore, when MRI is combined with velocity encoding phase-contrast (PC) imaging, one can accurately measure regional and central aortic stiffness by means of pulse wave velocity (PWV) analysis with MRI [12]. In this study, we sought to determine the extent of altered aortic stiffness in adolescent TS and MFS patients and whether altered stiffness is augmented by the presence of a bicuspid aortic valve (BAV), a commonly associated lesion in TS. Furthermore, we sought to investigate whether altered aortic stiffness properties influences the thoracic aorta differently in the TS and MFS patient populations. We hypothesized that (i) central aortic stiffness would be elevated in both groups and (ii) aortic stiffness would be independent of aortic size. Better understanding of aortic remodelling in patients with connective tissue disease may influence clinical surveillance strategies, timing of surgical procedures and risk assessment to prevent acute aortic events. METHODS This is a retrospective observational study of all TS and MFS patients at the Children’s Hospital Colorado who were referred for cardiac MRI evaluation between January 2014 and December 2017. Thirty-seven TS and 20 MFS patients with similar age and weight distribution were evaluated for thoracic aortic stiffness, flow haemodynamics and left ventricular (LV) function. Exclusion criteria included previous procedures on the thoracic aorta, aortic stenosis, coarctation or aortic arch hypoplasia, anti-hypertensive medication and valve disease. Control subjects included previously described healthy normotensive subjects [13]. This study was approved by the Colorado Multi-Institutional Review Board. Cardiac magnetic resonance imaging protocol A gradient echo ECG-gated sequence was applied to obtain tissue intensity and phase velocity maps using a 1.5- or 3.0-Tesla magnet (Magnetom Avanto, Siemens Medical Solutions, Erlangen, Germany; Ingenia, Philips Medical Systems, Best, Netherlands) using a phased-array body surface coil. A single plane of acquisition for flow haemodynamic evaluation was placed in an orthogonal fashion in the ascending aorta, approximately 1 cm above the sinotubular junction corresponding to the proximal descending thoracic aorta 3–5 cm below the origin of the left subclavian artery. To account for different growth linearity in TS and MFS patients and female exclusivity in patients with TS, aortopathy-specific Z-scores were calculated to avoid geometric overestimation [14–16]. A free breathing PC-MRI sequence was applied with Cartesian encoding and retrospective sorting (TR 14–28 ms/30–50 phases, TE 2.2–3.5 ms, matrix 160 × 256, flip angle 25°) with 100% k-space sampling and no further temporal interpolation. Depending on patient size and field of view (128–225 × 210–360 mm), the cross-sectional pixel resolution was 0.82 × 0.82–1.56 ×1.56 mm2 with a slice thickness of 5 mm. PC-MRI acquisition time for each plane varied depending on heart rate between 2 and 3 min. Velocity encoding values were adjusted according to the maximum velocities encountered during scout sequences to avoid aliasing artefact (typical values ranged from 100 to 250 cm/s). The LV-dimensional analysis was obtained from standard SSFP short-axis images with complete coverage of the ventricles from base to apex with standard volumetric and functional metrics indexed to body surface area (BSA). Aortic stiffness analysis We used 2 techniques to characterize local aortic stiffness: (i) flow–area (dQ/dA) method to assess local stiffness in the ascending aorta and descending aorta and (ii) wave propagation method (dx/dt) to evaluate the stiffness of the aortic arch globally (Fig. 1). Using flow–area method, flow and area waveforms were generated from time-frame-segmented respective PC and magnitude images for both ascending and descending aortic segments, as shown previously (Matlab Program; Mathworks, Inc., Natick, MA, USA) [13]. The flow–area diagrams were then employed to analyse segmental PWV by computation of dQ/dA slope using data points representing the early systole. Figure 1: View largeDownload slide A workflow diagram depicting the local aortic stiffness analysis using PWV. Phase-contrast magnetic resonance imaging magnitude (A) and velocity encoding images (B) positioned to transect orthogonally both the ascending and descending aortas were segmented to acquire respective area (C), flow (D) and time-dependent waveforms. (E) Flow–area diagrams are then constructed for flow–area method using PWV computation as the slope during the initial systolic phase. Flow propagation method was also applied to evaluate global aortic arch stiffness, which was performed by dividing the distance measured between 2 segmented lumens (dx) by time difference between 2 flow waveforms (dt). Ao: aorta; PWV: pulse wave velocity. Figure 1: View largeDownload slide A workflow diagram depicting the local aortic stiffness analysis using PWV. Phase-contrast magnetic resonance imaging magnitude (A) and velocity encoding images (B) positioned to transect orthogonally both the ascending and descending aortas were segmented to acquire respective area (C), flow (D) and time-dependent waveforms. (E) Flow–area diagrams are then constructed for flow–area method using PWV computation as the slope during the initial systolic phase. Flow propagation method was also applied to evaluate global aortic arch stiffness, which was performed by dividing the distance measured between 2 segmented lumens (dx) by time difference between 2 flow waveforms (dt). Ao: aorta; PWV: pulse wave velocity. Wave propagation was calculated using the time difference (dt) between 2 peak flow data points on temporally superimposed flow waveforms. The distance between 2 planes (dx) was measured along the luminal centreline between the ascending aorta and descending aorta. Aortic strain was measured in each aortic region using relative area change (RAC), defined as the difference between maximum and minimum areas divided by maximum value: (Amax−Amin)/Amax × 100%. Distensibility for all aortic segments was then computed as the ratio of RAC and pulse pressure. Blood pressure values were obtained prior to MRI evaluation using a pressure oscillometric technique either in clinic the day prior or in the MRI suite immediately prior to the MRI examination. Statistical analysis Analyses were performed in SAS (version 9.4 or higher; SAS Institute, Cary, NC, USA). All variables were checked for the distributional assumption of normality using normal plots, in addition to Kolmogorov–Smirnov and Shapiro–Wilk tests. Positively skewed variables were natural log-transformed for correlation analyses (linear regression models). Demographic, clinical and flow haemodynamic characteristics between individual groups (TS, MFS and control) were compared using the Kruskal–Wallis test or 1-way analysis of variance with subsequent specific pairwise analyses to assess the exact inter-group differences. The effect of a BAV in TS patients was assessed using the independent sample Student’s t-test for normally distributed continuous variables and the Wilcoxon-rank sum test for non-normally distributed datasets. Univariate linear regression models were used to examine association between aortic stiffness (PWV, RAC and distensibility) and aortic size adjusted for age, systolic blood pressure and BSA. Significance was based on a P-value <0.05. RESULTS Patient characteristics and haemodynamics Patient characteristics and haemodynamics are summarized in Table 1. Although the age was similar between groups, BSA was significantly elevated in MFS patients when compared with controls. Eighteen (49%) TS patients had a BAV. There was no significant difference in blood pressure metrics among the groups. Three patients with TS were identified to have an aberrant right subclavian artery and 4 patients with TS had a bovine aortic arch anatomy. Patients with TS had significantly lower BSA, indexed LV end-diastolic and end-systolic volumes when compared with controls and MFS patients (both P < 0.05). MFS patients exhibited lower LV ejection fraction when compared with both controls and TS (both P < 0.05). There were no differences between indexed LV mass and cardiac index. Table 1: Demographics and left ventricular haemodynamics TS (n = 37) MFS (n = 20) Control (n = 22) P-value Age (years) 16 ± 4 18 ± 5 15 ± 3 0.301 BSA (m2) 1.46 ± 0.22** 1.80 ± 0.51** 1.38 ± 0.31 0.030 Sex (female) 9 (45) 10 (45) SBP (mmHg) 113 ± 8 116 ± 6 115 ± 9 0.412 DBP (mmHg) 68 ± 5 66 ± 3 66 ± 6 0.209 BAV 18 (49) 0 0 EDVi (ml/m2) 73 ± 13** 101 ± 29 99 ± 43 0.003 ESVi (ml/m2) 31 ± 7**,* 48 ± 16 41 ± 19 0.001 SVi (ml/m2) 42 ± 7** 53 ± 15 54 ± 21 0.011 Mass-i (g/m2) 38 ± 7 47 ± 14 49 ± 26 0.064 CI (l/min/m2) 3.5 ± 0.6 3.9 ± 1.4 4.1 ± 2.1 0.289 EF (%) 58 ± 5* 52 ± 4* 58 ± 5 0.001 TS (n = 37) MFS (n = 20) Control (n = 22) P-value Age (years) 16 ± 4 18 ± 5 15 ± 3 0.301 BSA (m2) 1.46 ± 0.22** 1.80 ± 0.51** 1.38 ± 0.31 0.030 Sex (female) 9 (45) 10 (45) SBP (mmHg) 113 ± 8 116 ± 6 115 ± 9 0.412 DBP (mmHg) 68 ± 5 66 ± 3 66 ± 6 0.209 BAV 18 (49) 0 0 EDVi (ml/m2) 73 ± 13** 101 ± 29 99 ± 43 0.003 ESVi (ml/m2) 31 ± 7**,* 48 ± 16 41 ± 19 0.001 SVi (ml/m2) 42 ± 7** 53 ± 15 54 ± 21 0.011 Mass-i (g/m2) 38 ± 7 47 ± 14 49 ± 26 0.064 CI (l/min/m2) 3.5 ± 0.6 3.9 ± 1.4 4.1 ± 2.1 0.289 EF (%) 58 ± 5* 52 ± 4* 58 ± 5 0.001 Data are reported as n (%) and mean ± SD or median with interquartile ranges. * P < 0.01 from MFS and from control. ** P < 0.05 from MFS and from control. BAV: bicuspid aortic valve; BSA: body surface area; CI: cardiac index; DBP: diastolic blood pressure; EDVi: end-distolic volume index; EF: ejection fraction; ESVi: end-systolic volume index; Mass-i: mass index; MFS: Marfan Syndrome; SBP: systolic blood pressure; SD: standard deviation; SVi: stroke volume index; TS: Turner Syndrome. Table 1: Demographics and left ventricular haemodynamics TS (n = 37) MFS (n = 20) Control (n = 22) P-value Age (years) 16 ± 4 18 ± 5 15 ± 3 0.301 BSA (m2) 1.46 ± 0.22** 1.80 ± 0.51** 1.38 ± 0.31 0.030 Sex (female) 9 (45) 10 (45) SBP (mmHg) 113 ± 8 116 ± 6 115 ± 9 0.412 DBP (mmHg) 68 ± 5 66 ± 3 66 ± 6 0.209 BAV 18 (49) 0 0 EDVi (ml/m2) 73 ± 13** 101 ± 29 99 ± 43 0.003 ESVi (ml/m2) 31 ± 7**,* 48 ± 16 41 ± 19 0.001 SVi (ml/m2) 42 ± 7** 53 ± 15 54 ± 21 0.011 Mass-i (g/m2) 38 ± 7 47 ± 14 49 ± 26 0.064 CI (l/min/m2) 3.5 ± 0.6 3.9 ± 1.4 4.1 ± 2.1 0.289 EF (%) 58 ± 5* 52 ± 4* 58 ± 5 0.001 TS (n = 37) MFS (n = 20) Control (n = 22) P-value Age (years) 16 ± 4 18 ± 5 15 ± 3 0.301 BSA (m2) 1.46 ± 0.22** 1.80 ± 0.51** 1.38 ± 0.31 0.030 Sex (female) 9 (45) 10 (45) SBP (mmHg) 113 ± 8 116 ± 6 115 ± 9 0.412 DBP (mmHg) 68 ± 5 66 ± 3 66 ± 6 0.209 BAV 18 (49) 0 0 EDVi (ml/m2) 73 ± 13** 101 ± 29 99 ± 43 0.003 ESVi (ml/m2) 31 ± 7**,* 48 ± 16 41 ± 19 0.001 SVi (ml/m2) 42 ± 7** 53 ± 15 54 ± 21 0.011 Mass-i (g/m2) 38 ± 7 47 ± 14 49 ± 26 0.064 CI (l/min/m2) 3.5 ± 0.6 3.9 ± 1.4 4.1 ± 2.1 0.289 EF (%) 58 ± 5* 52 ± 4* 58 ± 5 0.001 Data are reported as n (%) and mean ± SD or median with interquartile ranges. * P < 0.01 from MFS and from control. ** P < 0.05 from MFS and from control. BAV: bicuspid aortic valve; BSA: body surface area; CI: cardiac index; DBP: diastolic blood pressure; EDVi: end-distolic volume index; EF: ejection fraction; ESVi: end-systolic volume index; Mass-i: mass index; MFS: Marfan Syndrome; SBP: systolic blood pressure; SD: standard deviation; SVi: stroke volume index; TS: Turner Syndrome. Aortic size and stiffness Aortic size and stiffness analyses are summarized in Table 2. Patients with MFS had significantly larger maximum and minimum luminal ascending aortic areas than the TS and control groups; however, this difference resolved when indexed to BSA. Stiffness metrics were most abnormal in the ascending aorta with both TS and MFS groups exhibiting signs of elevated central aortic stiffness. Table 2: Aortic stiffness analysis TS (n = 37) MFS (n = 20) Control (n = 22) P-value Ascending aorta  Amax (cm2) 4.7 ± 1.1* 6.9 ± 1.9* 5.3 ± 1.2 <0.001  Amin (cm2) 3.8 ± 1.1* 5.4 ± 1.7* 3.9 ± 0.8 0.001  Dmax (cm) 2.5 ± 0.4** 2.9 ± 0.5 2.6 ± 0.2 0.036  Dmax/BSA (cm/m2) 1.8 ± 0.4 1.8 ± 0.4 1.9 ± 0.5 0.458  Z-score 0.46 (−0.34 to 1.03)*,** 1.71 (1.03–1.82) 1.22 (1.05–1.70) 0.005  RAC (%) 21 ± 9* 22 ± 5** 29 ± 5 0.002  Distensibility (%/mmHg) 0.43 ± 0.19** 0.39 ± 0.09** 0.58 ± 0.19 0.022  PWV (m/s) 1.8 (1.2–2.4) 2.4 (1.2–2.9) 2.0 (1.8–2.5) 0.337 Descending aorta  Amax (cm2) 2.9 ± 0.8* 3.9 ± 1.4** 3.0 ± 0.7 0.002  Amin (cm2) 2.3 ± 0.8 3.2 ± 1.2* 2.2 ± 0.6 0.001  Dmax (cm) 1.9 ± 0.3* 2.2 ± 0.4** 1.9 ± 0.3 0.002  Dmax/BSA (cm/m2) 1.3 ± 0.2 1.2 ± 0.2 1.5 ± 0.6 0.253  Z-score 0.52 (0.03–1.18)* 1.20 (0.45–1.80) 1.37 (1.15–1.55) <0.001  RAC (%) 22 ± 6 18 ± 6* 25 ± 9 0.005  Distensibility (%/mmHg) 0.51 ± 0.15** 0.36 ± 0.14** 0.55 ± 17 0.019  PWV (m/s) 2.4 (1.8–3.3) 2.5 (1.9–3.7) 2.4 (1.9–3.6) 0.374 Aortic arch PWV (m/s) 2.7 (2.5–3.9)** 4.2 (3.0–6.3) * 1.9 (1.7–2.3) 0.001 TS (n = 37) MFS (n = 20) Control (n = 22) P-value Ascending aorta  Amax (cm2) 4.7 ± 1.1* 6.9 ± 1.9* 5.3 ± 1.2 <0.001  Amin (cm2) 3.8 ± 1.1* 5.4 ± 1.7* 3.9 ± 0.8 0.001  Dmax (cm) 2.5 ± 0.4** 2.9 ± 0.5 2.6 ± 0.2 0.036  Dmax/BSA (cm/m2) 1.8 ± 0.4 1.8 ± 0.4 1.9 ± 0.5 0.458  Z-score 0.46 (−0.34 to 1.03)*,** 1.71 (1.03–1.82) 1.22 (1.05–1.70) 0.005  RAC (%) 21 ± 9* 22 ± 5** 29 ± 5 0.002  Distensibility (%/mmHg) 0.43 ± 0.19** 0.39 ± 0.09** 0.58 ± 0.19 0.022  PWV (m/s) 1.8 (1.2–2.4) 2.4 (1.2–2.9) 2.0 (1.8–2.5) 0.337 Descending aorta  Amax (cm2) 2.9 ± 0.8* 3.9 ± 1.4** 3.0 ± 0.7 0.002  Amin (cm2) 2.3 ± 0.8 3.2 ± 1.2* 2.2 ± 0.6 0.001  Dmax (cm) 1.9 ± 0.3* 2.2 ± 0.4** 1.9 ± 0.3 0.002  Dmax/BSA (cm/m2) 1.3 ± 0.2 1.2 ± 0.2 1.5 ± 0.6 0.253  Z-score 0.52 (0.03–1.18)* 1.20 (0.45–1.80) 1.37 (1.15–1.55) <0.001  RAC (%) 22 ± 6 18 ± 6* 25 ± 9 0.005  Distensibility (%/mmHg) 0.51 ± 0.15** 0.36 ± 0.14** 0.55 ± 17 0.019  PWV (m/s) 2.4 (1.8–3.3) 2.5 (1.9–3.7) 2.4 (1.9–3.6) 0.374 Aortic arch PWV (m/s) 2.7 (2.5–3.9)** 4.2 (3.0–6.3) * 1.9 (1.7–2.3) 0.001 Data are reported as mean ± SD or median with interquartile ranges. * P < 0.01 from MFS and from control (the analysis of variance or the Kruskal–Wallis test). ** P < 0.05 from MFS and from control (the analysis of variance or the Kruskal–Wallis test). MFS: Marfan syndrome; PWV: pulse wave velocity; RAC: relative area change; SD: standard deviation; TS: Turner syndrome. Table 2: Aortic stiffness analysis TS (n = 37) MFS (n = 20) Control (n = 22) P-value Ascending aorta  Amax (cm2) 4.7 ± 1.1* 6.9 ± 1.9* 5.3 ± 1.2 <0.001  Amin (cm2) 3.8 ± 1.1* 5.4 ± 1.7* 3.9 ± 0.8 0.001  Dmax (cm) 2.5 ± 0.4** 2.9 ± 0.5 2.6 ± 0.2 0.036  Dmax/BSA (cm/m2) 1.8 ± 0.4 1.8 ± 0.4 1.9 ± 0.5 0.458  Z-score 0.46 (−0.34 to 1.03)*,** 1.71 (1.03–1.82) 1.22 (1.05–1.70) 0.005  RAC (%) 21 ± 9* 22 ± 5** 29 ± 5 0.002  Distensibility (%/mmHg) 0.43 ± 0.19** 0.39 ± 0.09** 0.58 ± 0.19 0.022  PWV (m/s) 1.8 (1.2–2.4) 2.4 (1.2–2.9) 2.0 (1.8–2.5) 0.337 Descending aorta  Amax (cm2) 2.9 ± 0.8* 3.9 ± 1.4** 3.0 ± 0.7 0.002  Amin (cm2) 2.3 ± 0.8 3.2 ± 1.2* 2.2 ± 0.6 0.001  Dmax (cm) 1.9 ± 0.3* 2.2 ± 0.4** 1.9 ± 0.3 0.002  Dmax/BSA (cm/m2) 1.3 ± 0.2 1.2 ± 0.2 1.5 ± 0.6 0.253  Z-score 0.52 (0.03–1.18)* 1.20 (0.45–1.80) 1.37 (1.15–1.55) <0.001  RAC (%) 22 ± 6 18 ± 6* 25 ± 9 0.005  Distensibility (%/mmHg) 0.51 ± 0.15** 0.36 ± 0.14** 0.55 ± 17 0.019  PWV (m/s) 2.4 (1.8–3.3) 2.5 (1.9–3.7) 2.4 (1.9–3.6) 0.374 Aortic arch PWV (m/s) 2.7 (2.5–3.9)** 4.2 (3.0–6.3) * 1.9 (1.7–2.3) 0.001 TS (n = 37) MFS (n = 20) Control (n = 22) P-value Ascending aorta  Amax (cm2) 4.7 ± 1.1* 6.9 ± 1.9* 5.3 ± 1.2 <0.001  Amin (cm2) 3.8 ± 1.1* 5.4 ± 1.7* 3.9 ± 0.8 0.001  Dmax (cm) 2.5 ± 0.4** 2.9 ± 0.5 2.6 ± 0.2 0.036  Dmax/BSA (cm/m2) 1.8 ± 0.4 1.8 ± 0.4 1.9 ± 0.5 0.458  Z-score 0.46 (−0.34 to 1.03)*,** 1.71 (1.03–1.82) 1.22 (1.05–1.70) 0.005  RAC (%) 21 ± 9* 22 ± 5** 29 ± 5 0.002  Distensibility (%/mmHg) 0.43 ± 0.19** 0.39 ± 0.09** 0.58 ± 0.19 0.022  PWV (m/s) 1.8 (1.2–2.4) 2.4 (1.2–2.9) 2.0 (1.8–2.5) 0.337 Descending aorta  Amax (cm2) 2.9 ± 0.8* 3.9 ± 1.4** 3.0 ± 0.7 0.002  Amin (cm2) 2.3 ± 0.8 3.2 ± 1.2* 2.2 ± 0.6 0.001  Dmax (cm) 1.9 ± 0.3* 2.2 ± 0.4** 1.9 ± 0.3 0.002  Dmax/BSA (cm/m2) 1.3 ± 0.2 1.2 ± 0.2 1.5 ± 0.6 0.253  Z-score 0.52 (0.03–1.18)* 1.20 (0.45–1.80) 1.37 (1.15–1.55) <0.001  RAC (%) 22 ± 6 18 ± 6* 25 ± 9 0.005  Distensibility (%/mmHg) 0.51 ± 0.15** 0.36 ± 0.14** 0.55 ± 17 0.019  PWV (m/s) 2.4 (1.8–3.3) 2.5 (1.9–3.7) 2.4 (1.9–3.6) 0.374 Aortic arch PWV (m/s) 2.7 (2.5–3.9)** 4.2 (3.0–6.3) * 1.9 (1.7–2.3) 0.001 Data are reported as mean ± SD or median with interquartile ranges. * P < 0.01 from MFS and from control (the analysis of variance or the Kruskal–Wallis test). ** P < 0.05 from MFS and from control (the analysis of variance or the Kruskal–Wallis test). MFS: Marfan syndrome; PWV: pulse wave velocity; RAC: relative area change; SD: standard deviation; TS: Turner syndrome. Both groups exhibited reduced aortic deformation, reflecting elevated stiffness. Figure 2 depicts examples of aortic wall deformation analysis from each cohort. Normal expansion of both the ascending aorta and descending aorta is demonstrated in the control case, whereas the MFS and TS examples show non-uniform, lower magnitude expansion, starting from a dilated baseline measurement, suggesting the presence of elevated aortic stiffness. RAC was significantly reduced in the ascending aorta when compared with controls in both TS (P < 0.01) and MFS (P < 0.05) patient groups. Ascending aortic distensibility was decreased in both groups with respect to controls (both P < 0.05). There was no significant difference in regional ascending aorta PWV between all 3 cohorts. Figure 2: View largeDownload slide Representative cases of aortic wall deformation analysis from phase-contrast magnetic resonance imaging magnitude images. Luminal contours are depicted from segmentation software and from corresponding A(t) wave forms. The control subject shows uniform and distinct expansions of both the ascending and descending aortas and features commonly associated with healthy compliant vessels. On the other hand, a representative Marfan Syndrome patient showing dilated, minimally expanding non-uniform expansion profile. A Turner Syndrome representative case showing similarly compromised distension suggesting early signs of reduced aortic strain and compliance. BSA: body surface area. Figure 2: View largeDownload slide Representative cases of aortic wall deformation analysis from phase-contrast magnetic resonance imaging magnitude images. Luminal contours are depicted from segmentation software and from corresponding A(t) wave forms. The control subject shows uniform and distinct expansions of both the ascending and descending aortas and features commonly associated with healthy compliant vessels. On the other hand, a representative Marfan Syndrome patient showing dilated, minimally expanding non-uniform expansion profile. A Turner Syndrome representative case showing similarly compromised distension suggesting early signs of reduced aortic strain and compliance. BSA: body surface area. In the descending aorta, patients with MFS had a significantly larger maximum and minimal aortic areas when compared with controls (P < 0.05) and TS (P < 0.01). Similarly, maximum aortic diameter was increased in MFS patients when compared with controls and TS (P < 0.05), but when diameter was indexed to BSA there were no differences between all considered groups. Z-score for the descending aortic diameter was significantly reduced in TS patients when compared with the MFS and control groups. The RAC was significantly reduced in the descending aorta in MFS patients when compared with controls only (P < 0.01), whereas distensibility was reduced in MFS patients when compared with both the control and TS groups (both P < 0.05). Again, no differences were observed in the regional descending aorta PWV. When considering the global aortic arch stiffness, patients with MFS had significantly elevated PWV when compared with controls (P < 0.01) and TS (P < 0.05). To investigate the potential stiffness augmenting effect of a BAV, we performed a subanalysis stratifying TS patients into 2 groups: TS with a trileaflet aortic valve and TS with a BAV (Table 3). Interestingly, there were no differences in standard aortic size metrics and any measured haemodynamic indices in both the ascending and descending aortas when compared with controls. Table 3: BAV in Turner syndrome BAV (n = 18) Non-BAV (n = 24) P-value Ascending aorta  Amax (cm2) 4.9 ± 1.1 4.7 ± 1.3 0.747  Amin (cm2) 3.9 ± 1.0 3.7 ± 1.3 0.613  Dmax (cm) 2.5 ± 0.3 2.5 ± 0.4 0.943  RAC (%) 19 ± 6 23 ± 10 0.355  Distensibility (%/mmHg) 0.51 ± 0.24 0.37 ± 0.11 0.272  PWV (m/s) 1.5 (1.2–2.1) 1.8 (1.4–2.4) 0.725 Descending aorta  Amax (cm2) 2.9 ± 0.6 2.9 ± 1.0 0.985  Amin (cm2) 2.3 ± 0.6 2.3 ± 1.0 0.948  Dmax (cm) 1.9 ± 0.2 1.9 ± 0.3 0.775  RAC (%) 22 ± 5 24 ± 7 0.421  Distensibility (%/mmHg) 0.52 ± 14 0.51 ± 0.16 0.845  PWV (m/s) 2.0 (1.5–3.1) 1.9 (1.3–3.1) 0.371 Aortic arch PWV (m/s) 2.6 (2.3–3.9) 2.8 (2.5–4.0) 0.417 BAV (n = 18) Non-BAV (n = 24) P-value Ascending aorta  Amax (cm2) 4.9 ± 1.1 4.7 ± 1.3 0.747  Amin (cm2) 3.9 ± 1.0 3.7 ± 1.3 0.613  Dmax (cm) 2.5 ± 0.3 2.5 ± 0.4 0.943  RAC (%) 19 ± 6 23 ± 10 0.355  Distensibility (%/mmHg) 0.51 ± 0.24 0.37 ± 0.11 0.272  PWV (m/s) 1.5 (1.2–2.1) 1.8 (1.4–2.4) 0.725 Descending aorta  Amax (cm2) 2.9 ± 0.6 2.9 ± 1.0 0.985  Amin (cm2) 2.3 ± 0.6 2.3 ± 1.0 0.948  Dmax (cm) 1.9 ± 0.2 1.9 ± 0.3 0.775  RAC (%) 22 ± 5 24 ± 7 0.421  Distensibility (%/mmHg) 0.52 ± 14 0.51 ± 0.16 0.845  PWV (m/s) 2.0 (1.5–3.1) 1.9 (1.3–3.1) 0.371 Aortic arch PWV (m/s) 2.6 (2.3–3.9) 2.8 (2.5–4.0) 0.417 Data are reported as mean ± SD or median with interquartile ranges. BAV: bicuspid aortic valve; PWV: pulse wave velocity; RAC: relative area change; SD: standard deviation. Table 3: BAV in Turner syndrome BAV (n = 18) Non-BAV (n = 24) P-value Ascending aorta  Amax (cm2) 4.9 ± 1.1 4.7 ± 1.3 0.747  Amin (cm2) 3.9 ± 1.0 3.7 ± 1.3 0.613  Dmax (cm) 2.5 ± 0.3 2.5 ± 0.4 0.943  RAC (%) 19 ± 6 23 ± 10 0.355  Distensibility (%/mmHg) 0.51 ± 0.24 0.37 ± 0.11 0.272  PWV (m/s) 1.5 (1.2–2.1) 1.8 (1.4–2.4) 0.725 Descending aorta  Amax (cm2) 2.9 ± 0.6 2.9 ± 1.0 0.985  Amin (cm2) 2.3 ± 0.6 2.3 ± 1.0 0.948  Dmax (cm) 1.9 ± 0.2 1.9 ± 0.3 0.775  RAC (%) 22 ± 5 24 ± 7 0.421  Distensibility (%/mmHg) 0.52 ± 14 0.51 ± 0.16 0.845  PWV (m/s) 2.0 (1.5–3.1) 1.9 (1.3–3.1) 0.371 Aortic arch PWV (m/s) 2.6 (2.3–3.9) 2.8 (2.5–4.0) 0.417 BAV (n = 18) Non-BAV (n = 24) P-value Ascending aorta  Amax (cm2) 4.9 ± 1.1 4.7 ± 1.3 0.747  Amin (cm2) 3.9 ± 1.0 3.7 ± 1.3 0.613  Dmax (cm) 2.5 ± 0.3 2.5 ± 0.4 0.943  RAC (%) 19 ± 6 23 ± 10 0.355  Distensibility (%/mmHg) 0.51 ± 0.24 0.37 ± 0.11 0.272  PWV (m/s) 1.5 (1.2–2.1) 1.8 (1.4–2.4) 0.725 Descending aorta  Amax (cm2) 2.9 ± 0.6 2.9 ± 1.0 0.985  Amin (cm2) 2.3 ± 0.6 2.3 ± 1.0 0.948  Dmax (cm) 1.9 ± 0.2 1.9 ± 0.3 0.775  RAC (%) 22 ± 5 24 ± 7 0.421  Distensibility (%/mmHg) 0.52 ± 14 0.51 ± 0.16 0.845  PWV (m/s) 2.0 (1.5–3.1) 1.9 (1.3–3.1) 0.371 Aortic arch PWV (m/s) 2.6 (2.3–3.9) 2.8 (2.5–4.0) 0.417 Data are reported as mean ± SD or median with interquartile ranges. BAV: bicuspid aortic valve; PWV: pulse wave velocity; RAC: relative area change; SD: standard deviation. Relationship between aortic stiffness and size To investigate the potential association between aortic stiffness in genetically induced aortopathies and aortic size, we performed linear regression analysis adjusted for age, BSA and systolic blood pressure to investigate relationship between considered aortic indices concerning only TS and MFS patients. No correlations existed between maximum ascending aortic diameter and locally measured RAC (r = −0.14, ß ± SE: −0.007 ± 0.009; P = 0.451), distensibility (r = −0.14, ß ± SE: −0.007 ± 0.009; P = 0.451) and PWV (r = 0.02, ß ± SE: 0.07 ± 0.68; P = 0.917). However, stiffness metrics measured in the descending aorta were strongly associated with aortic size. We observed a significant negative correlation between descending aortic RAC and maximum diameter (r = −0.766, ß ± SE: −0.015 ± 0.005; P = 0.007) (Fig. 3). Correspondingly, negative correlation was observed between distensibility and maximum diameter (r = −0.779, ß ± SE: −0.64 ± 0.23; P = 0.006). There was no correlation between local PWV and maximum diameter (r = 0.03, ß ± SE: 0.03 ± 0.02; P = 0.202). Figure 3: View largeDownload slide Scatter plots depicting the relationship between descending aortic size and local stiffness measures. The maximum aortic diameter correlated with relative area change (A) and distensibility (B), both representative of intrinsic geometry-dependent stiffness properties. Correlations were adjusted to age, body surface area and systolic blood pressure. Figure 3: View largeDownload slide Scatter plots depicting the relationship between descending aortic size and local stiffness measures. The maximum aortic diameter correlated with relative area change (A) and distensibility (B), both representative of intrinsic geometry-dependent stiffness properties. Correlations were adjusted to age, body surface area and systolic blood pressure. DISCUSSION Accelerated aortic dilation and stiffness have been recognized as major risk factors for aortic dissection in TS and MFS patients. Hence, frequent screening is recommended [2, 11]. This study indicates that (i) elevated central aortic stiffness is observed in teenage patients with TS and MFS despite normal indexed aortic diameters, (ii) TS patients demonstrate increased stiffness in the ascending aorta and arch, whereas the entire ascending thoracic aorta and descending thoracic aorta are uniformly affected in MFS patients. (iii) The presence of a BAV does not seem to augment aortic stiffness in teenage TS patients. Our results imply that TS and MFS patients undergo different patterns of aortic wall remodelling, that is focused in the proximal aorta in those with TS. Our results support the currently prevalent claims that risk stratification solely based on increasing aortic size and the presence of a BAV is insufficient for surveillance of teenage patients with TS and MFS, and that addition of comprehensive mapping of aortic biomechanical properties may prove beneficial [17, 18]. Elevated aortic stiffness has previously been described in a small study of preteenage TS patients using echocardiography and carotid-femoral PWV methods [19]. However, carotid-femoral methods are not reflective of central aortic stiffness and are subject to underlying assumptions regarding the intravascular distance and pulse wave reflections [20]. MRI-derived flow waveforms are currently considered the gold standard for non-invasive measurement of central aortic stiffness [12]. We applied MRI-derived geometric indices and found reduced RAC and distensibility in the ascending aorta but not in the descending aorta of TS patients. These findings echo the results of Devos et al. [17] who found the same pattern of reduced distensibility in an older group of TS patients. In our younger patient population, we applied the flow–area method, which allowed us to separately observe stiffness in the ascending and descending aorta. We did not find elevated regional PWV in the ascending aorta and descending aorta; however, the global PWV of the aortic arch as assessed by more typical flow area method was increased in TS patients when compared with controls. The aortic arch is, in general, prone to accelerated stiffness and atherosclerosis and can impose backward wave reflections mainly due to structural anatomy and geometric variations, predisposing it to non-laminar flow haemodynamics and vessel wall remodelling. Our findings suggest that abnormal stiffness in TS patients affects the ascending aorta and arch. This fits with the observation that the majority of dissections in TS population are Stanford Type-A dissections [21]. We found no effect of a BAV on our TS patients. This might be due to the predominant effect of the TS connective tissue disease on the proximal aorta; however, it may be that the contribution of the BAV aortopathy becomes more pronounced at a later age [17]. Larger, more comprehensive biomechanical analyses of the thoracic aorta are needed to aid the understanding of BAV-related aortopathy in patients with TS. Additionally, flow-based stiffness analysis may be influenced by the presence of a non-standard aortic arch anatomy, which is commonly associated with TS [22]. Flow haemodynamic patterns typically measured using wall shear stress have been shown to be associated with intrinsic aortic tissue properties in patients with a BAV [23]. Importantly, Arnold et al. [22] have described abnormal qualitative flow patterns along with regionally reduced wall shear stress in patients with TS using 4-dimensional flow MRI. Severe aortic dilation and aortic stiffness are also well recognized features in MFS [3, 24]. Results of our study indicate a comprehensive aortic stiffening process present already in young teenage MFS patients despite normal indexed aortic diameters. In our study, aortic stiffness was more pronounced in MFS patients than in TS patients, potentially justifying more frequent aortic surveillance for these patients. Our results are in keeping with those of Nollen et al. [24] and Westenberg et al. [25] who described elevated stiffness in MFS patients throughout the aorta. Stiffness indices measured separately for different thoracic aortic segments were significantly altered despite normal indexed aortic diameters. This finding begs the question whether stiffness indices are more predictive of dissection than aortic size. In this study, a significant association was observed in aortopathy patients between aortic size and stiffness only in the descending aorta when aortic size was adjusted to BSA, age and systolic blood pressure. We did not observe a similar relationship in the ascending aorta, implying that geometric and tissue characteristic properties might not be the only factors responsible for progressive aortic dilation in patients with congenital tissue disorders. Previous flow haemodynamic studies using 4-dimensional flow MRI techniques described disturbed thoracic aortic flow and shear forces in MFS patients [5, 26]. Non-uniform flow haemodynamic shear stress along with a large scale flow disturbance with vortices and helices have been associated with aortic remodelling, stiffness and endothelial injury in MFS [27]. Although both MFS and TS are characterized by diffused presence of abnormal aortic tissue, different responses in each aortic segment as dictated by disease-specific alteration within extracellular matrix likely lead to a different regional aortic wall response [21]. Lastly, the MRI analysis of ventricular function revealed reduced LV ejection fraction with preserved LV volumes. These findings are in agreement with a previous MRI study by De Backer et al. [28] who described a decreased LV function in young adults with MFS. The observed reduced LV ejection fraction possibly warrants monitoring of comprehensive systolic and diastolic function in MFS patients. With respect to patients with TS, our findings mirror previous results by Oz et al. [29] describing reduced LV volumes with preserved ejection fraction. Comprehensive deformation and strain analyses would be helpful to fully understand myocardial function and ventricular–vascular coupling in patients with MFS and TS. Limitations We recognize several limitations of this study. First, due to the non-invasive and retrospective nature of our study, we applied brachial blood pressure measurements in this study, which are not fully reflective of central aortic blood pressure and may affect our distensibility calculations. Second, our ascending aortic flow and area measurements might have been disturbed by aortic through-plane motion. We attempted to mitigate this phenomenon by selecting acquisition planes sufficiently far from the sinotubular junction. Third, patients underwent MRI analysis on 2 different scanning systems. Under ideal circumstances, the identical acquisition sequence and MRI vendor system should have been applied in each case since different magnetic field strengths potentially produce intersystem variability. However, previous studies have demonstrated that variable field strength has not been shown to alter the flow haemodynamic evaluation in great vessels [30]. Finally, more comprehensive aortic evaluation using abdominal images was not possible due to the small number of acquisitions in this region. Our future aortopathy studies will involve prospective comprehensive 4-dimensional flow and PC-MRI studies to longitudinally assess geometric, stiffness and flow haemodynamic nature of the aorta. CONCLUSION In summary, teenage TS and MFS patients already display early signs of aortic stiffness in the setting of normal indexed aortic diameters. In TS patients, the stiffness is focused in the ascending aorta, with a more diffuse abnormality found in MFS patients. Our study supports the claim that aortic dimension analysis should be complemented with dynamic stiffness-based measures to delineate clinically applicable risk factors for development of aortic dilation and dissection. PC-MRI is a non-invasive technique with increasing clinical availability, which is capable of comprehensive haemodynamic evaluation in the longitudinal follow-up of patients with genetically induced aortopathy. Funding This work was supported in part by The Jayden de Luca Foundation. Conflict of interest: none declared. REFERENCES 1 Hagan PG , Nienaber CA , Isselbacher EM , Bruckman D , Karavite DJ , Russman PL et al. The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease . JAMA 2000 ; 283 : 897 – 903 . 2 Nienaber CA , Powell JT. Management of acute aortic syndromes . Eur Heart J 2012 ; 33 : 26 – 35 . 3 Jondeau G , Detaint D , Tubach F , Arnoult F , Milleron O , Raoux F et al. Aortic event rate in the Marfan population: a cohort study . Circulation 2012 ; 125 : 226 – 32 . 4 Matura LA , Ho VB , Rosing DR , Bondy CA. Aortic dilatation and dissection in Turner syndrome . Circulation 2007 ; 116 : 1663 – 70 . 5 Geiger J , Hirtler D , Gottfried K , Rahman O , Bollache E , Barker AJ et al. Longitudinal evaluation of aortic hemodynamics in Marfan syndrome: new insights from a 4D flow cardiovascular magnetic resonance multi-year follow-up study . J Cardiovasc Magn Reson 2017 ; 19 : 33. 6 van der Palen RLF , Barker AJ , Bollache E , Garcia J , Rose MJ , van Ooij P et al. Altered aortic 3D hemodynamics and geometry in pediatric Marfan syndrome patients . J Cardiovasc Magn Reson 2017 ; 19 : 30. 7 Carlson M , Airhart N , Lopez L , Silberbach M. Moderate aortic enlargement and bicuspid aortic valve are associated with aortic dissection in Turner syndrome: report of the international Turner syndrome aortic dissection registry . Circulation 2012 ; 126 : 2220 – 6 . 8 Isselbacher EM , Bonaca MP , Di Eusanio M , Froehlich J , Bassone E , Sechtem U et al. Recurrent aortic dissection: observations from the International Registry of Aortic Dissection . 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A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine . J Am Coll Cardiol 2010 ; 55 : e27 – 129 . 12 Quail MA , Short R , Pandya B , Steeden JA , Khushnood A , Taylor AM et al. Abnormal wave reflections and left ventricular hypertrophy late after coarctation of the aorta repair . Hypertension 2017 ; 69 : 501 – 9 . 13 Schäfer M , Ivy DD , Abman SH , Barker AJ , Browne LP , Fonseca B et al. Apparent aortic stiffness in children with pulmonary arterial hypertension . Circ Cardiovasc Imaging 2017 ; 10 : e005817. 14 Quezada E , Lapidus J , Shaughnessy R , Chen Z , Silberbach M. Aortic dimensions in Turner syndrome . 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Am J Physiol Heart Circ Physiol 2006 ; 290 : H2385 – 92 . 19 De Groote K , Devos D , Van Herck K , De Wolf D , Van der Straaten S , Rietzschel E et al. Increased aortic stiffness in prepubertal girls with Turner syndrome . J Cardiol 2017 ; 69 : 201 – 7 . 20 Wentland AL , Grist TM , Wieben O. Review of MRI-based measurements of pulse wave velocity: a biomarker of arterial stiffness . Cardiovasc Diagn Ther 2014 ; 4 : 193 – 206 . 21 Bondy CA. Aortic dissection in Turner syndrome . Curr Opin Cardiol 2008 ; 23 : 519 – 26 . 22 Arnold R , Neu M , Hirtler D , Gimpel C , Markl M , Geiger J. Magnetic resonance imaging 4-D flow-based analysis of aortic hemodynamics in Turner syndrome . Pediatr Radiol 2017 ; 47 : 382 – 90 . 23 Guzzardi DG , Barker AJ , van Ooij P , Malaisrie SC , Puthumana JJ , Belke DD et al. Valve-related hemodynamics mediate human bicuspid aortopathy . J Am Coll Cardiol 2015 ; 66 : 892 – 900 . 24 Nollen GJ , Groenink M , Tijssen JGP , Van Der WEE , Mulder BJM. Aortic stiffness and diameter predict progressive aortic dilatation in patients with Marfan syndrome . Eur Heart J 2004 ; 25 : 1146 – 52 . 25 Westenberg JJ , Scholte AJ , Vaskova Z , van der Geest RJ , Groenink M , Labadie G et al. Age-related and regional changes of aortic stiffness in the Marfan syndrome: assessment with velocity-encoded MRI . J Magn Reson Imaging 2011 ; 34 : 526 – 31 . 26 Geiger J , Arnold R , Herzer L , Hirtler D , Stankovic Z , Russe M et al. Aortic wall shear stress in Marfan syndrome . Magn Reson Med 2012 ; 0 : 1 – 8 . 27 Davies PF. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology . Nat Rev Cardiol 2009 ; 6 : 16 – 26 . 28 De Backer JF , Devos D , Segers P , Matthys D , François K , Gillebert TC et al. Primary impairment of left ventricular function in Marfan syndrome . Int J Cardiol 2006 ; 112 : 353 – 8 . 29 Oz F , Cizgici AY , Ucar A , Karaayvaz EB , Kocaaga M , Bugra Z et al. Doppler-derived strain imaging detects left ventricular systolic dysfunction in children with Turner syndrome . Echocardiography 2014 ; 31 : 1017 – 22 . 30 Barker AJ , Roldán-Alzate A , Entezari P , Shah SJ , Chesler NC , Wieben O et al. Four-dimensional flow assessment of pulmonary artery flow and wall shear stress in adult pulmonary arterial hypertension: results from two institutions . Magn Reson Med 2014 ; 63 : 1904 – 13 . © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Cardio-Thoracic Surgery Oxford University Press

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Abstract

Abstract OBJECTIVES Turner syndrome (TS) and Marfan syndrome (MFS) are partially characterized by aortopathies with a risk of developing severe aortic dilation, stiffness and consequent dissection and aneurysm formation. The incidence of a bicuspid aortic valve (BAV) is also increased in TS. We investigated aortic stiffness in teenage TS and MFS patients and evaluated to what degree stiffness in TS patients is augmented by the presence of a BAV. METHODS Fifty-seven patients with TS (n = 37) and MFS (n = 20), as well as 22 controls with similar age and size distribution underwent evaluation of thoracic aortic stiffness using phase-contrast magnetic resonance imaging. Calculated stiffness indices including pulse wave velocity (PWV), distensibility and relative area change (RAC) were collected to characterize the ascending aorta and descending aorta. PWV was also determined to evaluate global aortic arch stiffness. RESULTS Patients with TS had reduced distensibility (0.43 vs 0.58%/mmHg, P < 0.05) and RAC (21 vs 29%, P < 0.01) in the ascending aorta when compared with normal controls. Similarly, patients with MFS had reduced ascending aortic distensibility (0.39 vs 0.58%/mmHg, P < 0.05) and RAC (22 vs 29%, P < 0.05). There were no differences in measured PWV in the ascending aorta. Patients with TS had significantly elevated PWV measured in the aortic arch when compared with controls (2.7 vs 1.9 m/s, P < 0.05). Patients with MFS had more prominent elevation in aortic arch PWV (4.2 vs 1.9 m/s, P < 0.01). The descending aortas had decreased distensibility (0.36 vs 0.55%/mmHg, P < 0.05) and RAC (18 vs 25%, P < 0.01) only in MFS patients. Additionally, 18 TS patients with a BAV were compared with 19 TS patients with a trileaflet aortic valve, without significant differences observed in any of the considered stiffness indices. CONCLUSIONS TS and MFS teenage patients display evidence of increased aortic stiffness. In TS patients, this is focused in the ascending aorta and is independent of the presence of a BAV. MFS patients display a generalized reduction in compliance of the entire aorta. Marfan syndrome , Turner syndrome , Aorta , Stiffness INTRODUCTION Turner syndrome (TS) and Marfan syndrome (MFS) are genetic disorders in which altered connective tissue composition may lead to severe aortopathy and increased risk for aortic dilation and dissection [1, 2]. Both patient groups represent the younger spectrum of patients at risk for developing these complications [3, 4]. The accelerated risk of developing an acute aortic event in TS and MFS is primarily due to altered extracellular matrix composition in aortic media manifesting as elevated aortic stiffness which along with altered haemodynamic shear forces may lead to development of intimal tears or rapidly progressive aortic dilation [5–7]. Consequently, early and extensive surgical intervention may be advocated to avoid an acute aortic events [8, 9]. Better understanding of aortic biomechanical properties is warranted to identify disease-specific indicators to guide therapy. Computed tomography (CT) and magnetic resonance imaging (MRI) are standard imaging modalities used for baseline evaluation and serial monitoring of TS and MFS patients [10]. CT allows comprehensive anatomical characterization of the thoracic aorta and is preferentially used for preoperative planning [11]. MRI provides detailed evaluation of aortic wall motion allowing for segmental analysis of aortic stiffness and avoids patient exposure to ionizing radiation. Furthermore, when MRI is combined with velocity encoding phase-contrast (PC) imaging, one can accurately measure regional and central aortic stiffness by means of pulse wave velocity (PWV) analysis with MRI [12]. In this study, we sought to determine the extent of altered aortic stiffness in adolescent TS and MFS patients and whether altered stiffness is augmented by the presence of a bicuspid aortic valve (BAV), a commonly associated lesion in TS. Furthermore, we sought to investigate whether altered aortic stiffness properties influences the thoracic aorta differently in the TS and MFS patient populations. We hypothesized that (i) central aortic stiffness would be elevated in both groups and (ii) aortic stiffness would be independent of aortic size. Better understanding of aortic remodelling in patients with connective tissue disease may influence clinical surveillance strategies, timing of surgical procedures and risk assessment to prevent acute aortic events. METHODS This is a retrospective observational study of all TS and MFS patients at the Children’s Hospital Colorado who were referred for cardiac MRI evaluation between January 2014 and December 2017. Thirty-seven TS and 20 MFS patients with similar age and weight distribution were evaluated for thoracic aortic stiffness, flow haemodynamics and left ventricular (LV) function. Exclusion criteria included previous procedures on the thoracic aorta, aortic stenosis, coarctation or aortic arch hypoplasia, anti-hypertensive medication and valve disease. Control subjects included previously described healthy normotensive subjects [13]. This study was approved by the Colorado Multi-Institutional Review Board. Cardiac magnetic resonance imaging protocol A gradient echo ECG-gated sequence was applied to obtain tissue intensity and phase velocity maps using a 1.5- or 3.0-Tesla magnet (Magnetom Avanto, Siemens Medical Solutions, Erlangen, Germany; Ingenia, Philips Medical Systems, Best, Netherlands) using a phased-array body surface coil. A single plane of acquisition for flow haemodynamic evaluation was placed in an orthogonal fashion in the ascending aorta, approximately 1 cm above the sinotubular junction corresponding to the proximal descending thoracic aorta 3–5 cm below the origin of the left subclavian artery. To account for different growth linearity in TS and MFS patients and female exclusivity in patients with TS, aortopathy-specific Z-scores were calculated to avoid geometric overestimation [14–16]. A free breathing PC-MRI sequence was applied with Cartesian encoding and retrospective sorting (TR 14–28 ms/30–50 phases, TE 2.2–3.5 ms, matrix 160 × 256, flip angle 25°) with 100% k-space sampling and no further temporal interpolation. Depending on patient size and field of view (128–225 × 210–360 mm), the cross-sectional pixel resolution was 0.82 × 0.82–1.56 ×1.56 mm2 with a slice thickness of 5 mm. PC-MRI acquisition time for each plane varied depending on heart rate between 2 and 3 min. Velocity encoding values were adjusted according to the maximum velocities encountered during scout sequences to avoid aliasing artefact (typical values ranged from 100 to 250 cm/s). The LV-dimensional analysis was obtained from standard SSFP short-axis images with complete coverage of the ventricles from base to apex with standard volumetric and functional metrics indexed to body surface area (BSA). Aortic stiffness analysis We used 2 techniques to characterize local aortic stiffness: (i) flow–area (dQ/dA) method to assess local stiffness in the ascending aorta and descending aorta and (ii) wave propagation method (dx/dt) to evaluate the stiffness of the aortic arch globally (Fig. 1). Using flow–area method, flow and area waveforms were generated from time-frame-segmented respective PC and magnitude images for both ascending and descending aortic segments, as shown previously (Matlab Program; Mathworks, Inc., Natick, MA, USA) [13]. The flow–area diagrams were then employed to analyse segmental PWV by computation of dQ/dA slope using data points representing the early systole. Figure 1: View largeDownload slide A workflow diagram depicting the local aortic stiffness analysis using PWV. Phase-contrast magnetic resonance imaging magnitude (A) and velocity encoding images (B) positioned to transect orthogonally both the ascending and descending aortas were segmented to acquire respective area (C), flow (D) and time-dependent waveforms. (E) Flow–area diagrams are then constructed for flow–area method using PWV computation as the slope during the initial systolic phase. Flow propagation method was also applied to evaluate global aortic arch stiffness, which was performed by dividing the distance measured between 2 segmented lumens (dx) by time difference between 2 flow waveforms (dt). Ao: aorta; PWV: pulse wave velocity. Figure 1: View largeDownload slide A workflow diagram depicting the local aortic stiffness analysis using PWV. Phase-contrast magnetic resonance imaging magnitude (A) and velocity encoding images (B) positioned to transect orthogonally both the ascending and descending aortas were segmented to acquire respective area (C), flow (D) and time-dependent waveforms. (E) Flow–area diagrams are then constructed for flow–area method using PWV computation as the slope during the initial systolic phase. Flow propagation method was also applied to evaluate global aortic arch stiffness, which was performed by dividing the distance measured between 2 segmented lumens (dx) by time difference between 2 flow waveforms (dt). Ao: aorta; PWV: pulse wave velocity. Wave propagation was calculated using the time difference (dt) between 2 peak flow data points on temporally superimposed flow waveforms. The distance between 2 planes (dx) was measured along the luminal centreline between the ascending aorta and descending aorta. Aortic strain was measured in each aortic region using relative area change (RAC), defined as the difference between maximum and minimum areas divided by maximum value: (Amax−Amin)/Amax × 100%. Distensibility for all aortic segments was then computed as the ratio of RAC and pulse pressure. Blood pressure values were obtained prior to MRI evaluation using a pressure oscillometric technique either in clinic the day prior or in the MRI suite immediately prior to the MRI examination. Statistical analysis Analyses were performed in SAS (version 9.4 or higher; SAS Institute, Cary, NC, USA). All variables were checked for the distributional assumption of normality using normal plots, in addition to Kolmogorov–Smirnov and Shapiro–Wilk tests. Positively skewed variables were natural log-transformed for correlation analyses (linear regression models). Demographic, clinical and flow haemodynamic characteristics between individual groups (TS, MFS and control) were compared using the Kruskal–Wallis test or 1-way analysis of variance with subsequent specific pairwise analyses to assess the exact inter-group differences. The effect of a BAV in TS patients was assessed using the independent sample Student’s t-test for normally distributed continuous variables and the Wilcoxon-rank sum test for non-normally distributed datasets. Univariate linear regression models were used to examine association between aortic stiffness (PWV, RAC and distensibility) and aortic size adjusted for age, systolic blood pressure and BSA. Significance was based on a P-value <0.05. RESULTS Patient characteristics and haemodynamics Patient characteristics and haemodynamics are summarized in Table 1. Although the age was similar between groups, BSA was significantly elevated in MFS patients when compared with controls. Eighteen (49%) TS patients had a BAV. There was no significant difference in blood pressure metrics among the groups. Three patients with TS were identified to have an aberrant right subclavian artery and 4 patients with TS had a bovine aortic arch anatomy. Patients with TS had significantly lower BSA, indexed LV end-diastolic and end-systolic volumes when compared with controls and MFS patients (both P < 0.05). MFS patients exhibited lower LV ejection fraction when compared with both controls and TS (both P < 0.05). There were no differences between indexed LV mass and cardiac index. Table 1: Demographics and left ventricular haemodynamics TS (n = 37) MFS (n = 20) Control (n = 22) P-value Age (years) 16 ± 4 18 ± 5 15 ± 3 0.301 BSA (m2) 1.46 ± 0.22** 1.80 ± 0.51** 1.38 ± 0.31 0.030 Sex (female) 9 (45) 10 (45) SBP (mmHg) 113 ± 8 116 ± 6 115 ± 9 0.412 DBP (mmHg) 68 ± 5 66 ± 3 66 ± 6 0.209 BAV 18 (49) 0 0 EDVi (ml/m2) 73 ± 13** 101 ± 29 99 ± 43 0.003 ESVi (ml/m2) 31 ± 7**,* 48 ± 16 41 ± 19 0.001 SVi (ml/m2) 42 ± 7** 53 ± 15 54 ± 21 0.011 Mass-i (g/m2) 38 ± 7 47 ± 14 49 ± 26 0.064 CI (l/min/m2) 3.5 ± 0.6 3.9 ± 1.4 4.1 ± 2.1 0.289 EF (%) 58 ± 5* 52 ± 4* 58 ± 5 0.001 TS (n = 37) MFS (n = 20) Control (n = 22) P-value Age (years) 16 ± 4 18 ± 5 15 ± 3 0.301 BSA (m2) 1.46 ± 0.22** 1.80 ± 0.51** 1.38 ± 0.31 0.030 Sex (female) 9 (45) 10 (45) SBP (mmHg) 113 ± 8 116 ± 6 115 ± 9 0.412 DBP (mmHg) 68 ± 5 66 ± 3 66 ± 6 0.209 BAV 18 (49) 0 0 EDVi (ml/m2) 73 ± 13** 101 ± 29 99 ± 43 0.003 ESVi (ml/m2) 31 ± 7**,* 48 ± 16 41 ± 19 0.001 SVi (ml/m2) 42 ± 7** 53 ± 15 54 ± 21 0.011 Mass-i (g/m2) 38 ± 7 47 ± 14 49 ± 26 0.064 CI (l/min/m2) 3.5 ± 0.6 3.9 ± 1.4 4.1 ± 2.1 0.289 EF (%) 58 ± 5* 52 ± 4* 58 ± 5 0.001 Data are reported as n (%) and mean ± SD or median with interquartile ranges. * P < 0.01 from MFS and from control. ** P < 0.05 from MFS and from control. BAV: bicuspid aortic valve; BSA: body surface area; CI: cardiac index; DBP: diastolic blood pressure; EDVi: end-distolic volume index; EF: ejection fraction; ESVi: end-systolic volume index; Mass-i: mass index; MFS: Marfan Syndrome; SBP: systolic blood pressure; SD: standard deviation; SVi: stroke volume index; TS: Turner Syndrome. Table 1: Demographics and left ventricular haemodynamics TS (n = 37) MFS (n = 20) Control (n = 22) P-value Age (years) 16 ± 4 18 ± 5 15 ± 3 0.301 BSA (m2) 1.46 ± 0.22** 1.80 ± 0.51** 1.38 ± 0.31 0.030 Sex (female) 9 (45) 10 (45) SBP (mmHg) 113 ± 8 116 ± 6 115 ± 9 0.412 DBP (mmHg) 68 ± 5 66 ± 3 66 ± 6 0.209 BAV 18 (49) 0 0 EDVi (ml/m2) 73 ± 13** 101 ± 29 99 ± 43 0.003 ESVi (ml/m2) 31 ± 7**,* 48 ± 16 41 ± 19 0.001 SVi (ml/m2) 42 ± 7** 53 ± 15 54 ± 21 0.011 Mass-i (g/m2) 38 ± 7 47 ± 14 49 ± 26 0.064 CI (l/min/m2) 3.5 ± 0.6 3.9 ± 1.4 4.1 ± 2.1 0.289 EF (%) 58 ± 5* 52 ± 4* 58 ± 5 0.001 TS (n = 37) MFS (n = 20) Control (n = 22) P-value Age (years) 16 ± 4 18 ± 5 15 ± 3 0.301 BSA (m2) 1.46 ± 0.22** 1.80 ± 0.51** 1.38 ± 0.31 0.030 Sex (female) 9 (45) 10 (45) SBP (mmHg) 113 ± 8 116 ± 6 115 ± 9 0.412 DBP (mmHg) 68 ± 5 66 ± 3 66 ± 6 0.209 BAV 18 (49) 0 0 EDVi (ml/m2) 73 ± 13** 101 ± 29 99 ± 43 0.003 ESVi (ml/m2) 31 ± 7**,* 48 ± 16 41 ± 19 0.001 SVi (ml/m2) 42 ± 7** 53 ± 15 54 ± 21 0.011 Mass-i (g/m2) 38 ± 7 47 ± 14 49 ± 26 0.064 CI (l/min/m2) 3.5 ± 0.6 3.9 ± 1.4 4.1 ± 2.1 0.289 EF (%) 58 ± 5* 52 ± 4* 58 ± 5 0.001 Data are reported as n (%) and mean ± SD or median with interquartile ranges. * P < 0.01 from MFS and from control. ** P < 0.05 from MFS and from control. BAV: bicuspid aortic valve; BSA: body surface area; CI: cardiac index; DBP: diastolic blood pressure; EDVi: end-distolic volume index; EF: ejection fraction; ESVi: end-systolic volume index; Mass-i: mass index; MFS: Marfan Syndrome; SBP: systolic blood pressure; SD: standard deviation; SVi: stroke volume index; TS: Turner Syndrome. Aortic size and stiffness Aortic size and stiffness analyses are summarized in Table 2. Patients with MFS had significantly larger maximum and minimum luminal ascending aortic areas than the TS and control groups; however, this difference resolved when indexed to BSA. Stiffness metrics were most abnormal in the ascending aorta with both TS and MFS groups exhibiting signs of elevated central aortic stiffness. Table 2: Aortic stiffness analysis TS (n = 37) MFS (n = 20) Control (n = 22) P-value Ascending aorta  Amax (cm2) 4.7 ± 1.1* 6.9 ± 1.9* 5.3 ± 1.2 <0.001  Amin (cm2) 3.8 ± 1.1* 5.4 ± 1.7* 3.9 ± 0.8 0.001  Dmax (cm) 2.5 ± 0.4** 2.9 ± 0.5 2.6 ± 0.2 0.036  Dmax/BSA (cm/m2) 1.8 ± 0.4 1.8 ± 0.4 1.9 ± 0.5 0.458  Z-score 0.46 (−0.34 to 1.03)*,** 1.71 (1.03–1.82) 1.22 (1.05–1.70) 0.005  RAC (%) 21 ± 9* 22 ± 5** 29 ± 5 0.002  Distensibility (%/mmHg) 0.43 ± 0.19** 0.39 ± 0.09** 0.58 ± 0.19 0.022  PWV (m/s) 1.8 (1.2–2.4) 2.4 (1.2–2.9) 2.0 (1.8–2.5) 0.337 Descending aorta  Amax (cm2) 2.9 ± 0.8* 3.9 ± 1.4** 3.0 ± 0.7 0.002  Amin (cm2) 2.3 ± 0.8 3.2 ± 1.2* 2.2 ± 0.6 0.001  Dmax (cm) 1.9 ± 0.3* 2.2 ± 0.4** 1.9 ± 0.3 0.002  Dmax/BSA (cm/m2) 1.3 ± 0.2 1.2 ± 0.2 1.5 ± 0.6 0.253  Z-score 0.52 (0.03–1.18)* 1.20 (0.45–1.80) 1.37 (1.15–1.55) <0.001  RAC (%) 22 ± 6 18 ± 6* 25 ± 9 0.005  Distensibility (%/mmHg) 0.51 ± 0.15** 0.36 ± 0.14** 0.55 ± 17 0.019  PWV (m/s) 2.4 (1.8–3.3) 2.5 (1.9–3.7) 2.4 (1.9–3.6) 0.374 Aortic arch PWV (m/s) 2.7 (2.5–3.9)** 4.2 (3.0–6.3) * 1.9 (1.7–2.3) 0.001 TS (n = 37) MFS (n = 20) Control (n = 22) P-value Ascending aorta  Amax (cm2) 4.7 ± 1.1* 6.9 ± 1.9* 5.3 ± 1.2 <0.001  Amin (cm2) 3.8 ± 1.1* 5.4 ± 1.7* 3.9 ± 0.8 0.001  Dmax (cm) 2.5 ± 0.4** 2.9 ± 0.5 2.6 ± 0.2 0.036  Dmax/BSA (cm/m2) 1.8 ± 0.4 1.8 ± 0.4 1.9 ± 0.5 0.458  Z-score 0.46 (−0.34 to 1.03)*,** 1.71 (1.03–1.82) 1.22 (1.05–1.70) 0.005  RAC (%) 21 ± 9* 22 ± 5** 29 ± 5 0.002  Distensibility (%/mmHg) 0.43 ± 0.19** 0.39 ± 0.09** 0.58 ± 0.19 0.022  PWV (m/s) 1.8 (1.2–2.4) 2.4 (1.2–2.9) 2.0 (1.8–2.5) 0.337 Descending aorta  Amax (cm2) 2.9 ± 0.8* 3.9 ± 1.4** 3.0 ± 0.7 0.002  Amin (cm2) 2.3 ± 0.8 3.2 ± 1.2* 2.2 ± 0.6 0.001  Dmax (cm) 1.9 ± 0.3* 2.2 ± 0.4** 1.9 ± 0.3 0.002  Dmax/BSA (cm/m2) 1.3 ± 0.2 1.2 ± 0.2 1.5 ± 0.6 0.253  Z-score 0.52 (0.03–1.18)* 1.20 (0.45–1.80) 1.37 (1.15–1.55) <0.001  RAC (%) 22 ± 6 18 ± 6* 25 ± 9 0.005  Distensibility (%/mmHg) 0.51 ± 0.15** 0.36 ± 0.14** 0.55 ± 17 0.019  PWV (m/s) 2.4 (1.8–3.3) 2.5 (1.9–3.7) 2.4 (1.9–3.6) 0.374 Aortic arch PWV (m/s) 2.7 (2.5–3.9)** 4.2 (3.0–6.3) * 1.9 (1.7–2.3) 0.001 Data are reported as mean ± SD or median with interquartile ranges. * P < 0.01 from MFS and from control (the analysis of variance or the Kruskal–Wallis test). ** P < 0.05 from MFS and from control (the analysis of variance or the Kruskal–Wallis test). MFS: Marfan syndrome; PWV: pulse wave velocity; RAC: relative area change; SD: standard deviation; TS: Turner syndrome. Table 2: Aortic stiffness analysis TS (n = 37) MFS (n = 20) Control (n = 22) P-value Ascending aorta  Amax (cm2) 4.7 ± 1.1* 6.9 ± 1.9* 5.3 ± 1.2 <0.001  Amin (cm2) 3.8 ± 1.1* 5.4 ± 1.7* 3.9 ± 0.8 0.001  Dmax (cm) 2.5 ± 0.4** 2.9 ± 0.5 2.6 ± 0.2 0.036  Dmax/BSA (cm/m2) 1.8 ± 0.4 1.8 ± 0.4 1.9 ± 0.5 0.458  Z-score 0.46 (−0.34 to 1.03)*,** 1.71 (1.03–1.82) 1.22 (1.05–1.70) 0.005  RAC (%) 21 ± 9* 22 ± 5** 29 ± 5 0.002  Distensibility (%/mmHg) 0.43 ± 0.19** 0.39 ± 0.09** 0.58 ± 0.19 0.022  PWV (m/s) 1.8 (1.2–2.4) 2.4 (1.2–2.9) 2.0 (1.8–2.5) 0.337 Descending aorta  Amax (cm2) 2.9 ± 0.8* 3.9 ± 1.4** 3.0 ± 0.7 0.002  Amin (cm2) 2.3 ± 0.8 3.2 ± 1.2* 2.2 ± 0.6 0.001  Dmax (cm) 1.9 ± 0.3* 2.2 ± 0.4** 1.9 ± 0.3 0.002  Dmax/BSA (cm/m2) 1.3 ± 0.2 1.2 ± 0.2 1.5 ± 0.6 0.253  Z-score 0.52 (0.03–1.18)* 1.20 (0.45–1.80) 1.37 (1.15–1.55) <0.001  RAC (%) 22 ± 6 18 ± 6* 25 ± 9 0.005  Distensibility (%/mmHg) 0.51 ± 0.15** 0.36 ± 0.14** 0.55 ± 17 0.019  PWV (m/s) 2.4 (1.8–3.3) 2.5 (1.9–3.7) 2.4 (1.9–3.6) 0.374 Aortic arch PWV (m/s) 2.7 (2.5–3.9)** 4.2 (3.0–6.3) * 1.9 (1.7–2.3) 0.001 TS (n = 37) MFS (n = 20) Control (n = 22) P-value Ascending aorta  Amax (cm2) 4.7 ± 1.1* 6.9 ± 1.9* 5.3 ± 1.2 <0.001  Amin (cm2) 3.8 ± 1.1* 5.4 ± 1.7* 3.9 ± 0.8 0.001  Dmax (cm) 2.5 ± 0.4** 2.9 ± 0.5 2.6 ± 0.2 0.036  Dmax/BSA (cm/m2) 1.8 ± 0.4 1.8 ± 0.4 1.9 ± 0.5 0.458  Z-score 0.46 (−0.34 to 1.03)*,** 1.71 (1.03–1.82) 1.22 (1.05–1.70) 0.005  RAC (%) 21 ± 9* 22 ± 5** 29 ± 5 0.002  Distensibility (%/mmHg) 0.43 ± 0.19** 0.39 ± 0.09** 0.58 ± 0.19 0.022  PWV (m/s) 1.8 (1.2–2.4) 2.4 (1.2–2.9) 2.0 (1.8–2.5) 0.337 Descending aorta  Amax (cm2) 2.9 ± 0.8* 3.9 ± 1.4** 3.0 ± 0.7 0.002  Amin (cm2) 2.3 ± 0.8 3.2 ± 1.2* 2.2 ± 0.6 0.001  Dmax (cm) 1.9 ± 0.3* 2.2 ± 0.4** 1.9 ± 0.3 0.002  Dmax/BSA (cm/m2) 1.3 ± 0.2 1.2 ± 0.2 1.5 ± 0.6 0.253  Z-score 0.52 (0.03–1.18)* 1.20 (0.45–1.80) 1.37 (1.15–1.55) <0.001  RAC (%) 22 ± 6 18 ± 6* 25 ± 9 0.005  Distensibility (%/mmHg) 0.51 ± 0.15** 0.36 ± 0.14** 0.55 ± 17 0.019  PWV (m/s) 2.4 (1.8–3.3) 2.5 (1.9–3.7) 2.4 (1.9–3.6) 0.374 Aortic arch PWV (m/s) 2.7 (2.5–3.9)** 4.2 (3.0–6.3) * 1.9 (1.7–2.3) 0.001 Data are reported as mean ± SD or median with interquartile ranges. * P < 0.01 from MFS and from control (the analysis of variance or the Kruskal–Wallis test). ** P < 0.05 from MFS and from control (the analysis of variance or the Kruskal–Wallis test). MFS: Marfan syndrome; PWV: pulse wave velocity; RAC: relative area change; SD: standard deviation; TS: Turner syndrome. Both groups exhibited reduced aortic deformation, reflecting elevated stiffness. Figure 2 depicts examples of aortic wall deformation analysis from each cohort. Normal expansion of both the ascending aorta and descending aorta is demonstrated in the control case, whereas the MFS and TS examples show non-uniform, lower magnitude expansion, starting from a dilated baseline measurement, suggesting the presence of elevated aortic stiffness. RAC was significantly reduced in the ascending aorta when compared with controls in both TS (P < 0.01) and MFS (P < 0.05) patient groups. Ascending aortic distensibility was decreased in both groups with respect to controls (both P < 0.05). There was no significant difference in regional ascending aorta PWV between all 3 cohorts. Figure 2: View largeDownload slide Representative cases of aortic wall deformation analysis from phase-contrast magnetic resonance imaging magnitude images. Luminal contours are depicted from segmentation software and from corresponding A(t) wave forms. The control subject shows uniform and distinct expansions of both the ascending and descending aortas and features commonly associated with healthy compliant vessels. On the other hand, a representative Marfan Syndrome patient showing dilated, minimally expanding non-uniform expansion profile. A Turner Syndrome representative case showing similarly compromised distension suggesting early signs of reduced aortic strain and compliance. BSA: body surface area. Figure 2: View largeDownload slide Representative cases of aortic wall deformation analysis from phase-contrast magnetic resonance imaging magnitude images. Luminal contours are depicted from segmentation software and from corresponding A(t) wave forms. The control subject shows uniform and distinct expansions of both the ascending and descending aortas and features commonly associated with healthy compliant vessels. On the other hand, a representative Marfan Syndrome patient showing dilated, minimally expanding non-uniform expansion profile. A Turner Syndrome representative case showing similarly compromised distension suggesting early signs of reduced aortic strain and compliance. BSA: body surface area. In the descending aorta, patients with MFS had a significantly larger maximum and minimal aortic areas when compared with controls (P < 0.05) and TS (P < 0.01). Similarly, maximum aortic diameter was increased in MFS patients when compared with controls and TS (P < 0.05), but when diameter was indexed to BSA there were no differences between all considered groups. Z-score for the descending aortic diameter was significantly reduced in TS patients when compared with the MFS and control groups. The RAC was significantly reduced in the descending aorta in MFS patients when compared with controls only (P < 0.01), whereas distensibility was reduced in MFS patients when compared with both the control and TS groups (both P < 0.05). Again, no differences were observed in the regional descending aorta PWV. When considering the global aortic arch stiffness, patients with MFS had significantly elevated PWV when compared with controls (P < 0.01) and TS (P < 0.05). To investigate the potential stiffness augmenting effect of a BAV, we performed a subanalysis stratifying TS patients into 2 groups: TS with a trileaflet aortic valve and TS with a BAV (Table 3). Interestingly, there were no differences in standard aortic size metrics and any measured haemodynamic indices in both the ascending and descending aortas when compared with controls. Table 3: BAV in Turner syndrome BAV (n = 18) Non-BAV (n = 24) P-value Ascending aorta  Amax (cm2) 4.9 ± 1.1 4.7 ± 1.3 0.747  Amin (cm2) 3.9 ± 1.0 3.7 ± 1.3 0.613  Dmax (cm) 2.5 ± 0.3 2.5 ± 0.4 0.943  RAC (%) 19 ± 6 23 ± 10 0.355  Distensibility (%/mmHg) 0.51 ± 0.24 0.37 ± 0.11 0.272  PWV (m/s) 1.5 (1.2–2.1) 1.8 (1.4–2.4) 0.725 Descending aorta  Amax (cm2) 2.9 ± 0.6 2.9 ± 1.0 0.985  Amin (cm2) 2.3 ± 0.6 2.3 ± 1.0 0.948  Dmax (cm) 1.9 ± 0.2 1.9 ± 0.3 0.775  RAC (%) 22 ± 5 24 ± 7 0.421  Distensibility (%/mmHg) 0.52 ± 14 0.51 ± 0.16 0.845  PWV (m/s) 2.0 (1.5–3.1) 1.9 (1.3–3.1) 0.371 Aortic arch PWV (m/s) 2.6 (2.3–3.9) 2.8 (2.5–4.0) 0.417 BAV (n = 18) Non-BAV (n = 24) P-value Ascending aorta  Amax (cm2) 4.9 ± 1.1 4.7 ± 1.3 0.747  Amin (cm2) 3.9 ± 1.0 3.7 ± 1.3 0.613  Dmax (cm) 2.5 ± 0.3 2.5 ± 0.4 0.943  RAC (%) 19 ± 6 23 ± 10 0.355  Distensibility (%/mmHg) 0.51 ± 0.24 0.37 ± 0.11 0.272  PWV (m/s) 1.5 (1.2–2.1) 1.8 (1.4–2.4) 0.725 Descending aorta  Amax (cm2) 2.9 ± 0.6 2.9 ± 1.0 0.985  Amin (cm2) 2.3 ± 0.6 2.3 ± 1.0 0.948  Dmax (cm) 1.9 ± 0.2 1.9 ± 0.3 0.775  RAC (%) 22 ± 5 24 ± 7 0.421  Distensibility (%/mmHg) 0.52 ± 14 0.51 ± 0.16 0.845  PWV (m/s) 2.0 (1.5–3.1) 1.9 (1.3–3.1) 0.371 Aortic arch PWV (m/s) 2.6 (2.3–3.9) 2.8 (2.5–4.0) 0.417 Data are reported as mean ± SD or median with interquartile ranges. BAV: bicuspid aortic valve; PWV: pulse wave velocity; RAC: relative area change; SD: standard deviation. Table 3: BAV in Turner syndrome BAV (n = 18) Non-BAV (n = 24) P-value Ascending aorta  Amax (cm2) 4.9 ± 1.1 4.7 ± 1.3 0.747  Amin (cm2) 3.9 ± 1.0 3.7 ± 1.3 0.613  Dmax (cm) 2.5 ± 0.3 2.5 ± 0.4 0.943  RAC (%) 19 ± 6 23 ± 10 0.355  Distensibility (%/mmHg) 0.51 ± 0.24 0.37 ± 0.11 0.272  PWV (m/s) 1.5 (1.2–2.1) 1.8 (1.4–2.4) 0.725 Descending aorta  Amax (cm2) 2.9 ± 0.6 2.9 ± 1.0 0.985  Amin (cm2) 2.3 ± 0.6 2.3 ± 1.0 0.948  Dmax (cm) 1.9 ± 0.2 1.9 ± 0.3 0.775  RAC (%) 22 ± 5 24 ± 7 0.421  Distensibility (%/mmHg) 0.52 ± 14 0.51 ± 0.16 0.845  PWV (m/s) 2.0 (1.5–3.1) 1.9 (1.3–3.1) 0.371 Aortic arch PWV (m/s) 2.6 (2.3–3.9) 2.8 (2.5–4.0) 0.417 BAV (n = 18) Non-BAV (n = 24) P-value Ascending aorta  Amax (cm2) 4.9 ± 1.1 4.7 ± 1.3 0.747  Amin (cm2) 3.9 ± 1.0 3.7 ± 1.3 0.613  Dmax (cm) 2.5 ± 0.3 2.5 ± 0.4 0.943  RAC (%) 19 ± 6 23 ± 10 0.355  Distensibility (%/mmHg) 0.51 ± 0.24 0.37 ± 0.11 0.272  PWV (m/s) 1.5 (1.2–2.1) 1.8 (1.4–2.4) 0.725 Descending aorta  Amax (cm2) 2.9 ± 0.6 2.9 ± 1.0 0.985  Amin (cm2) 2.3 ± 0.6 2.3 ± 1.0 0.948  Dmax (cm) 1.9 ± 0.2 1.9 ± 0.3 0.775  RAC (%) 22 ± 5 24 ± 7 0.421  Distensibility (%/mmHg) 0.52 ± 14 0.51 ± 0.16 0.845  PWV (m/s) 2.0 (1.5–3.1) 1.9 (1.3–3.1) 0.371 Aortic arch PWV (m/s) 2.6 (2.3–3.9) 2.8 (2.5–4.0) 0.417 Data are reported as mean ± SD or median with interquartile ranges. BAV: bicuspid aortic valve; PWV: pulse wave velocity; RAC: relative area change; SD: standard deviation. Relationship between aortic stiffness and size To investigate the potential association between aortic stiffness in genetically induced aortopathies and aortic size, we performed linear regression analysis adjusted for age, BSA and systolic blood pressure to investigate relationship between considered aortic indices concerning only TS and MFS patients. No correlations existed between maximum ascending aortic diameter and locally measured RAC (r = −0.14, ß ± SE: −0.007 ± 0.009; P = 0.451), distensibility (r = −0.14, ß ± SE: −0.007 ± 0.009; P = 0.451) and PWV (r = 0.02, ß ± SE: 0.07 ± 0.68; P = 0.917). However, stiffness metrics measured in the descending aorta were strongly associated with aortic size. We observed a significant negative correlation between descending aortic RAC and maximum diameter (r = −0.766, ß ± SE: −0.015 ± 0.005; P = 0.007) (Fig. 3). Correspondingly, negative correlation was observed between distensibility and maximum diameter (r = −0.779, ß ± SE: −0.64 ± 0.23; P = 0.006). There was no correlation between local PWV and maximum diameter (r = 0.03, ß ± SE: 0.03 ± 0.02; P = 0.202). Figure 3: View largeDownload slide Scatter plots depicting the relationship between descending aortic size and local stiffness measures. The maximum aortic diameter correlated with relative area change (A) and distensibility (B), both representative of intrinsic geometry-dependent stiffness properties. Correlations were adjusted to age, body surface area and systolic blood pressure. Figure 3: View largeDownload slide Scatter plots depicting the relationship between descending aortic size and local stiffness measures. The maximum aortic diameter correlated with relative area change (A) and distensibility (B), both representative of intrinsic geometry-dependent stiffness properties. Correlations were adjusted to age, body surface area and systolic blood pressure. DISCUSSION Accelerated aortic dilation and stiffness have been recognized as major risk factors for aortic dissection in TS and MFS patients. Hence, frequent screening is recommended [2, 11]. This study indicates that (i) elevated central aortic stiffness is observed in teenage patients with TS and MFS despite normal indexed aortic diameters, (ii) TS patients demonstrate increased stiffness in the ascending aorta and arch, whereas the entire ascending thoracic aorta and descending thoracic aorta are uniformly affected in MFS patients. (iii) The presence of a BAV does not seem to augment aortic stiffness in teenage TS patients. Our results imply that TS and MFS patients undergo different patterns of aortic wall remodelling, that is focused in the proximal aorta in those with TS. Our results support the currently prevalent claims that risk stratification solely based on increasing aortic size and the presence of a BAV is insufficient for surveillance of teenage patients with TS and MFS, and that addition of comprehensive mapping of aortic biomechanical properties may prove beneficial [17, 18]. Elevated aortic stiffness has previously been described in a small study of preteenage TS patients using echocardiography and carotid-femoral PWV methods [19]. However, carotid-femoral methods are not reflective of central aortic stiffness and are subject to underlying assumptions regarding the intravascular distance and pulse wave reflections [20]. MRI-derived flow waveforms are currently considered the gold standard for non-invasive measurement of central aortic stiffness [12]. We applied MRI-derived geometric indices and found reduced RAC and distensibility in the ascending aorta but not in the descending aorta of TS patients. These findings echo the results of Devos et al. [17] who found the same pattern of reduced distensibility in an older group of TS patients. In our younger patient population, we applied the flow–area method, which allowed us to separately observe stiffness in the ascending and descending aorta. We did not find elevated regional PWV in the ascending aorta and descending aorta; however, the global PWV of the aortic arch as assessed by more typical flow area method was increased in TS patients when compared with controls. The aortic arch is, in general, prone to accelerated stiffness and atherosclerosis and can impose backward wave reflections mainly due to structural anatomy and geometric variations, predisposing it to non-laminar flow haemodynamics and vessel wall remodelling. Our findings suggest that abnormal stiffness in TS patients affects the ascending aorta and arch. This fits with the observation that the majority of dissections in TS population are Stanford Type-A dissections [21]. We found no effect of a BAV on our TS patients. This might be due to the predominant effect of the TS connective tissue disease on the proximal aorta; however, it may be that the contribution of the BAV aortopathy becomes more pronounced at a later age [17]. Larger, more comprehensive biomechanical analyses of the thoracic aorta are needed to aid the understanding of BAV-related aortopathy in patients with TS. Additionally, flow-based stiffness analysis may be influenced by the presence of a non-standard aortic arch anatomy, which is commonly associated with TS [22]. Flow haemodynamic patterns typically measured using wall shear stress have been shown to be associated with intrinsic aortic tissue properties in patients with a BAV [23]. Importantly, Arnold et al. [22] have described abnormal qualitative flow patterns along with regionally reduced wall shear stress in patients with TS using 4-dimensional flow MRI. Severe aortic dilation and aortic stiffness are also well recognized features in MFS [3, 24]. Results of our study indicate a comprehensive aortic stiffening process present already in young teenage MFS patients despite normal indexed aortic diameters. In our study, aortic stiffness was more pronounced in MFS patients than in TS patients, potentially justifying more frequent aortic surveillance for these patients. Our results are in keeping with those of Nollen et al. [24] and Westenberg et al. [25] who described elevated stiffness in MFS patients throughout the aorta. Stiffness indices measured separately for different thoracic aortic segments were significantly altered despite normal indexed aortic diameters. This finding begs the question whether stiffness indices are more predictive of dissection than aortic size. In this study, a significant association was observed in aortopathy patients between aortic size and stiffness only in the descending aorta when aortic size was adjusted to BSA, age and systolic blood pressure. We did not observe a similar relationship in the ascending aorta, implying that geometric and tissue characteristic properties might not be the only factors responsible for progressive aortic dilation in patients with congenital tissue disorders. Previous flow haemodynamic studies using 4-dimensional flow MRI techniques described disturbed thoracic aortic flow and shear forces in MFS patients [5, 26]. Non-uniform flow haemodynamic shear stress along with a large scale flow disturbance with vortices and helices have been associated with aortic remodelling, stiffness and endothelial injury in MFS [27]. Although both MFS and TS are characterized by diffused presence of abnormal aortic tissue, different responses in each aortic segment as dictated by disease-specific alteration within extracellular matrix likely lead to a different regional aortic wall response [21]. Lastly, the MRI analysis of ventricular function revealed reduced LV ejection fraction with preserved LV volumes. These findings are in agreement with a previous MRI study by De Backer et al. [28] who described a decreased LV function in young adults with MFS. The observed reduced LV ejection fraction possibly warrants monitoring of comprehensive systolic and diastolic function in MFS patients. With respect to patients with TS, our findings mirror previous results by Oz et al. [29] describing reduced LV volumes with preserved ejection fraction. Comprehensive deformation and strain analyses would be helpful to fully understand myocardial function and ventricular–vascular coupling in patients with MFS and TS. Limitations We recognize several limitations of this study. First, due to the non-invasive and retrospective nature of our study, we applied brachial blood pressure measurements in this study, which are not fully reflective of central aortic blood pressure and may affect our distensibility calculations. Second, our ascending aortic flow and area measurements might have been disturbed by aortic through-plane motion. We attempted to mitigate this phenomenon by selecting acquisition planes sufficiently far from the sinotubular junction. Third, patients underwent MRI analysis on 2 different scanning systems. Under ideal circumstances, the identical acquisition sequence and MRI vendor system should have been applied in each case since different magnetic field strengths potentially produce intersystem variability. However, previous studies have demonstrated that variable field strength has not been shown to alter the flow haemodynamic evaluation in great vessels [30]. Finally, more comprehensive aortic evaluation using abdominal images was not possible due to the small number of acquisitions in this region. Our future aortopathy studies will involve prospective comprehensive 4-dimensional flow and PC-MRI studies to longitudinally assess geometric, stiffness and flow haemodynamic nature of the aorta. CONCLUSION In summary, teenage TS and MFS patients already display early signs of aortic stiffness in the setting of normal indexed aortic diameters. In TS patients, the stiffness is focused in the ascending aorta, with a more diffuse abnormality found in MFS patients. Our study supports the claim that aortic dimension analysis should be complemented with dynamic stiffness-based measures to delineate clinically applicable risk factors for development of aortic dilation and dissection. PC-MRI is a non-invasive technique with increasing clinical availability, which is capable of comprehensive haemodynamic evaluation in the longitudinal follow-up of patients with genetically induced aortopathy. Funding This work was supported in part by The Jayden de Luca Foundation. Conflict of interest: none declared. REFERENCES 1 Hagan PG , Nienaber CA , Isselbacher EM , Bruckman D , Karavite DJ , Russman PL et al. The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease . JAMA 2000 ; 283 : 897 – 903 . 2 Nienaber CA , Powell JT. Management of acute aortic syndromes . Eur Heart J 2012 ; 33 : 26 – 35 . 3 Jondeau G , Detaint D , Tubach F , Arnoult F , Milleron O , Raoux F et al. Aortic event rate in the Marfan population: a cohort study . Circulation 2012 ; 125 : 226 – 32 . 4 Matura LA , Ho VB , Rosing DR , Bondy CA. Aortic dilatation and dissection in Turner syndrome . 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Doppler-derived strain imaging detects left ventricular systolic dysfunction in children with Turner syndrome . Echocardiography 2014 ; 31 : 1017 – 22 . 30 Barker AJ , Roldán-Alzate A , Entezari P , Shah SJ , Chesler NC , Wieben O et al. Four-dimensional flow assessment of pulmonary artery flow and wall shear stress in adult pulmonary arterial hypertension: results from two institutions . Magn Reson Med 2014 ; 63 : 1904 – 13 . © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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European Journal of Cardio-Thoracic SurgeryOxford University Press

Published: Apr 19, 2018

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