Guala et al. Journal of Cardiovascular Magnetic Resonance (2019) 21:63 https://doi.org/10.1186/s12968-019-0572-1 RESEARCH Open Access Decreased rotational flow and circumferential wall shear stress as early markers of descending aorta dilation in Marfan syndrome: a 4D flow CMR study A. Guala1†, G. Teixido-Tura1*† , L. Dux-Santoy1, C. Granato1, A. Ruiz-Muñoz1, F. Valente1, L. Galian-Gay1, L. Gutiérrez1, T. González-Alujas1, K. M. Johnson2, O. Wieben2, A. Sao Avilés1, A. Evangelista1 and J. Rodriguez-Palomares1 Abstract Background: Diseases of the descending aorta have emerged as a clinical issue in Marfan syndrome following improvements in proximal aorta surgical treatment and the consequent increase in life expectancy. Although a role for hemodynamic alterations in the etiology of descending aorta disease in Marfan patients has been suggested, whether flow characteristics may be useful as early markers remains to be determined. Methods: Seventy-five Marfan patients and 48 healthy subjects were prospectively enrolled. In- and through-plane vortexes were computed by 4D flow cardiovascular magnetic resonance (CMR) in the thoracic aorta through the quantification of in-plane rotational flow and systolic flow reversal ratio, respectively. Regional pulse wave velocity and axial and circumferential wall shear stress maps were also computed. Results: In-plane rotational flow and circumferential wall shear stress were reduced in Marfan patients in the distal ascending aorta and in proximal descending aorta, even in the 20 patients free of aortic dilation. Multivariate analysis showed reduced in-plane rotational flow to be independently related to descending aorta pulse wave velocity. Conversely, systolic flow reversal ratio and axial wall shear stress were altered in unselected Marfan patients but not in the subgroup without dilation. In multivariate regression analysis proximal descending aorta axial (p = 0.014) and circumferential (p = 0.034) wall shear stress were independently related to local diameter. Conclusions: Reduced rotational flow is present in the aorta of Marfan patients even in the absence of dilation, is related to aortic stiffness and drives abnormal circumferential wall shear stress. Axial and circumferential wall shear stress are independently related to proximal descending aorta dilation beyond clinical factors. In-plane rotational flow and circumferential wall shear stress may be considered as an early marker of descending aorta dilation in Marfan patients. Keywords: Marfan syndrome, 4D flow CMR, Helical flow, Descending aorta, Aortic aneurysm, Wall shear stress (WSS) * Correspondence: gteixido@vhebron.net † A. Guala and G. Teixido-Tura contributed equally to this work. 1 Hospital Universitari Vall d’Hebron, Department of Cardiology. CIBER-CV. Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Paseo Vall d’Hebron 119-129, 08035 Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Guala et al. Journal of Cardiovascular Magnetic Resonance (2019) 21:63 Page 2 of 11 Introduction committee and written informed consent was obtained Marfan syndrome is a hereditary connective tissue dis- from all participants. order caused by a mutation in the FBN1 gene. The remarkable advances in diagnosis, treatment and elective Cardiovascular magnetic resonance protocol aortic root replacement resulted in a great reduction in CMR studies were performed on a clinical 1.5 T scanner proximal aorta fatal events in Marfan patients [1, 2], (Signa, GE Healthcare, Waukesha, Wisconsin , USA). The prompting an impressive rise in life expectancy [3]. As a protocol included balanced steady-state free-precession result, diseases of the descending aorta (DAo) have (bSSFP) cine imaging to assess aortic diameter, 2D phase emerged as a clinical issue, either in the form of a primary contrast images of the aortic valve to evaluate aortic valve complication of the DAo or in the follow-up of patients disease and a 4D phase-contrast CMR (4D flow CMR) ac- with previous surgical prophylactic ascending aorta re- quisition for hemodynamics analysis. A radially- placement [1, 2, 4]. Longitudinal data in Marfan patients undersampled acquisition (PC VIPR) with 5-point bal- showed that 63% of aortic dissections involved the distal anced velocity encoding [10] with retrospective electrocar- aorta, in 31% of which the involvement was exclusive [4]. diogram (ECG)-gating during free-breathing was used for Although aortic diameter has been identified as a risk 4D flow imaging of the entire thoracic aorta in ≈ 10 min marker for DAo complications [1, 2, 4], 47% of type B total scan time. Data were acquired with an eight-channel aortic dissections occur with DAo diameter < 27 mm [1]. cardiac coil (HD Cardiac, GE Healthcare) using the follow- As a consequence, other risk markers beyond aortic ing parameters: velocity encoding (VENC) 200 cm/s, field diameter are needed to better define the risk of DAo of view 400x400x400 mm, acquisition matrix complications in these patients [4]. 160x160x160, voxel size 2.5 × 2.5 × 2.5 mm. This data set For this purpose, 4D flow cardiovascular magnetic res- was reconstructed offline according to the nominal tem- onance (CMR) studies evaluating hemodynamics and poral resolution (5xTR) of each patient, yielding a temporal wall shear stress (WSS) have recently been conducted. resolution of 25.5 ± 5 ms. Data were corrected for back- Wang et al. reported reduced helical flow in the aortic ground phase from concomitant gradients, eddy currents root in MFS patients [5], while other studies demon- and trajectory errors of the 3D radial acquired k-space strated the role of proximal DAo vortexes in the creation [10]. Brachial systolic (SBP) and diastolic (DBP) pressures of areas of low WSS localized in the proximal DAo [6– were taken immediately after the CMR study. 8], which were related to local dilation [6] in a region where most type B dissections occur [6]. However, sev- Hemodynamics evaluation eral aspects have not been investigated to date. Firstly, Patient-specific 3D geometric models of the aorta were no study made a quantitative evaluation of these flow semi-automatically reconstructed from Phase Contrast abnormalities. Thus, previous semi-quantitative analyses Magnetic Resonance Angiograms (PC MRA) using ITK- were limited for differentiating a pathologic from a Snap [11] and used to mask the velocity data. PC MRA physiologic proximal DAo vortex [6, 9], and characteriz- was used to identify the sinotubular junction (STJ), first ing these vortexes in terms of direction and intensity. and last supra-aortic vessels and location of the pulmonary Moreover, no studies to date have evaluated these flow artery bifurcation. The height of the pulmonary artery bi- disturbances in MFS without aortic dilation, thereby lim- furcation served to separate proximal and distal regions of iting the possibility of assessing whether these flow char- both ascending (AAo) and DAo. Aortic centerline was acteristics may be early markers of aortic disease. computed and 20 perpendicular analysis planes were iden- We aimed to investigate blood flow and WSS patterns tified between the STJ and end of the proximal DAo. Eight by 4D flow CMR in the thoracic aorta of Marfan patients equidistant analysis planes were located in the AAo, 4 in with and without aortic dilation to identify potential the aortic arch and 8 in the proximal DAo, yielding average early markers of DAo disease. distances between analysis planes of 10 mm in the AAo, 7.2 mm in aortic arch and 7.4 mm in the proximal DAo. Methods Hemodynamics characterization was made in each plane Study population using custom-designed Matlab (Mathworks, Natick, Massa- Seventy-five genetically-confirmed Marfan syndrome chusetts,USA) code. In-plane rotational flow (IRF), also patients were prospectively recruited from our Aortic called circumferential circulation [12], a widely-used Unit. Inclusion criteria were: age > 18 years and absence marker, was quantified using circulation, a parameter used of bicuspid aortic valve, significant valve dysfunction (< in fluid dynamics to quantify flow rotation. IRF is a surro- grade III aortic regurgitation and stenosis) and previous gate marker of helical flow that quantifies its circumferen- heart or aortic surgery and contraindication for CMR . tial part by isolating the rotational component of the Furthermore, 48 healthy subjects were recruited as con- velocity field residing in the plane [13]. In-plane rotational trols. The study was approved by the local ethics flow was computed at peak systole, averaging through one Guala et al. Journal of Cardiovascular Magnetic Resonance (2019) 21:63 Page 3 of 11 Fig. 1 Flow field visualization. Top: visualization of the velocity field as a series of sagittal images showing flow streamlines at four successive systolic time frames (from a to d, 27 ms time step) of a representative Marfan patient with dilation of the proximal descending aorta (DAo). Streamline visualization was obtained with CVI42, Circle Cardiovascular Imaging Inc., Calgary, Canada. Bottom: through-plane (red, backward with |velocity| > 10 cm/s; blue, forward with |velocity| > 10 cm/s) and in-plane (red, higher velocity, same velocity scale as top boxes.) velocity components of a proximal DAo section of the same patient. B = back, F = front, I = inner, IRV = in-plane rotational flow, O = outer,SFRR = systolic flow reversal ratio Guala et al. Journal of Cardiovascular Magnetic Resonance (2019) 21:63 Page 4 of 11 time frame before and two frames after peak systole to miti- Statistical analysis gate noise. Systolic flow reversal ratio (SFRR) was calculated Continuous demographic variables were expressed as as the ratio of forward to backward through-plane systolic mean ± standard deviation if they presented a normal volumes [14]. This parameter, also known as systolic back- distribution, and as median [1st-3rd] quartiles otherwise. ward flow, offers quantification of the strength of vortexes Categorical variables were presented as frequency (per- rotating around an axis perpendicular to the centerline. Fig- centage). The Kolmogorov-Smirnov test was used to ure 1 permits visualization of the differences between in- evaluate distribution normality. Differences between plane (IRF) and through-plane (SFRR) flow rotation pat- groups for continuous parameters were assessed by Stu- terns in a representative Marfan patient with proximal DAo dent’s t-test if normally distributed, and Mann-Whitney dilation. The maximum through-plane velocity at the STJ U test otherwise. Chi-square test was used for categor- was also extracted. ical variables. Multivariate linear or logistic regression Axial and circumferential WSS were computed as pre- analyses with a backward selection procedure and multi- viously described [15, 16]. In order to compute collinearity test were used to identify statistically- population-averaged WSS maps, axial and circumferen- significant associations. Independent variables entered tial WSS were averaged at 8 regions around the lumen the model if p < 0.15 in univariate analyses. A two-tailed contour of each cross-sectional plane. Data were aligned p value < 0.05 was considered statistically significant. for all patients using the inner aortic curvature as a ref- SPSS 21.0 (Statistical Package for the Social Sciences, erence. Axial and circumferential WSS were averaged International Business Machines, Inc., Armonk, New over meaningful regions to test whether they are inde- York, USA) was used for the analysis. pendently related to proximal DAo diameter. Axial WSS was averaged in the left/left-inner region of the proximal Results DAo (planes 14 and 15, where dilation is most likely to Demographic characteristics be present), while circumferential WSS was averaged on Demographic characteristics, aortic diameters and regional the circular section 14. Thus, averaging was made in the aortic stiffness in healthy subjects and Marfan patients with region where the peak curvature and most flow abnor- and without aortic dilation are shown in Table 1. malities are seen [7]. As expected, Marfan patients had larger aortic root and AAo and DAo diameters. Twenty Marfan patients Aortic mechanical properties free of dilation of the aortic root and the proximal DAo Regional aortic pulse wave velocity was computed separ- were grouped as non-dilated Marfan subjects. Non- ately in the ascending and descending aorta as previously dilated Marfan had larger aortic root diameter compared described [17]. Briefly, local velocity waveforms were with healthy subjects; however, aortic root z-score was extracted at 100 equally-distributed analysis planes and low and within normal range. DBP was slightly but not transit time was calculated by wavelet analysis as recently significantly higher in Marfan compared to healthy sub- proposed [18]. jects . Mean aortic valve regurgitant fraction and max- imum velocity were slightly higher and lower, Aortic diameters and definitions of dilation respectively, in Marfan compared to healthy subjects . The three cusp-to-cusp diameters were measured at the However, differences were clinically insignificant since aortic root level at the end-diastolic frame and the max- the values fell within normal range. As previously re- imum was considered for analysis. Aortic root dilation ported [17, 21, 22], Marfarn patients presented increased was considered when z-score, based on age, body surface AAo and DAo stiffness (measured here as an increase in area (BSA) and sex as reported by Devereux et al. [19], pulse wave velocity) compared with healthy subjects, was > 2. Diameter of the DAo at pulmonary artery level even in the absence of dilation. was extracted from PC MRA. DAo dilation was defined as a diameter > 90th percentile of the sex-, age- and Hemodynamics BSA-matched population published by Rogers et al. [20]. IRF, which is the in-plane projection of helical flow, was The non-dilated MFS subgroup included patients not substantially lower in Marfan patients at the distal AAo, presenting with dilation of either the aortic root or the aortic arch and proximal DAo (see top-left panel of Fig. 2 DAo. and Additional file 1: Table S1). Differences were statistically-significant in most planes between distal Aortic valve disease AAo and proximal DAo, even after the inclusion in PC images of the aortic valve were used to evaluate aor- multivariate analysis of sex, height, BSA, DBP, aortic tic valve disease. Aortic valve stenosis was evaluated by valve regurgitant fraction and maximum velocity as in- extracting the maximum velocity and aortic valve regur- dependent variables. Interestingly, Marfan transitioned gitation via regurgitant fraction. from clockwise to counter-clockwise rotation (i.e. from Guala et al. Journal of Cardiovascular Magnetic Resonance (2019) 21:63 Page 5 of 11 Table 1 Demographics and clinical data Healthy Marfan patients Subjects ALL Non-dilated Marfan Dilated Marfan N 48 75 p-values 20 p-values 55 p-values age [years] 39 ± 12 37 ± 13 0.327 34 ± 10 0.104 38 ± 14 0.611 Sex [N, (%) men] 31 (65) 42 (56) 0.026 5 (25) 0.002 37 (67) 0.165 Height [cm] 172 ± 8 180 ± 11 < 0.001 177 ± 9 0.024 182 ± 11 < 0.001 BSA [m2] 1.84 ± 0.16 1.91 ± 0.22 0.052 1.85 ± 0.22 0.931 1.95 ± 0.22 0.011 SBP [mmHg] 126 ± 18 128 ± 17 0.523 130 ± 15 0.381 128 ± 18 0.704 DBP [mmHg] 70 ± 12 74 ± 12 0.069 76 ± 11 0.051 74 ± 12 0.176 AoV regurgitant fraction [%] 1±1 2±5 0.087 1±1 0.593 3±5 0.035 AoV peak velocity [m/s] 1.2 ± 0.2 1.1 ± 0.2 0.067 1.1 ± 0.2 0.057 1.1 ± 0.3 0.122 Aortic root diameter [mm] 30.0 ± 4.0 38.6 ± 5.0 < 0.001 34.0 ± 3.1 < 0.001 40.3 ± 4.7 < 0.001 Aortic root z-score −0.73 ± 1.06 2.32 ± 1.99 < 0.001 0.69 ± 0.94 < 0.001 2.88 ± 1.79 < 0.001 AAo diameter [mm] 30.2 ± 4.1 35.2 ± 6.4 < 0.001 30.1 ± 6.1 0.958 37.1 ± 5.8 < 0.001 Proximal DAo diameter [mm] 23.2 ± 2.9 25.1 ± 4.4 0.009 22.2 ± 2.1 0.174 26.2 ± 4.5 < 0.001 AAo PWV [m/s] 5.3 ± 1.9 7.3 ± 2.8 < 0.001 7.1 ± 2.2 0.002 7.3 ± 3.0 < 0.001 DAo PWV [m/s] 7.2 ± 2.2 10.8 ± 4.5 < 0.001 10.2 ± 4.0 < 0.001 11.1 ± 4.6 < 0.001 Demographic characteristics, aortic diameters and ascending and descending pulse wave velocities (PWV) of healthy volunteers (HV), Marfan patients (ALL MFS) and the subset of Marfan patients with neither aortic root nor descending aorta dilation (Non-dilated Marfan). SBP, DBP: systolic and diastolic blood pressure, respectively. AAo represents ascending and DAo descending aorta. Data are presented as mean ± SD or number (percentage). P-values report the comparison with healthy controls positive to negative IRF) in the middle of the proximal and diastolic blood pressure, aortic root z-score and DAo. Conversely, in healthy subjects , IRF was progres- AAo PWV (see Table 2). In multivariate analysis cor- sively reduced when moving distally, without presenting rected for BSA and maximum velocity at the sinotubular inversion of rotation direction, at least before pulmonary junction, average IRF was independently related to DAo bifurcation level. SFRR, also called systolic backward flow PWV (p = 0.041). being a measurement of backward systolic flow and thus systolic through-plane vorticity, tended to be higher in Marfan compared to healthy subjects in the proximal Axial and circumferential WSS maps AAo and DAo, but not in the aortic arch (see bottom-left Axial WSS maps showed lower values in Marfan patients panel of Fig. 2). However, on multivariate analysis, none of compared to healthy subjects in the proximal AAo, espe- these tendencies reached statistical significance. cially in the outer region, and in the left-inner region of Interestingly, even the subset of 20 Marfan patients the proximal DAo (see top row of Fig. 3). Circumferen- without aortic dilation presented a markedly lower IRF at tial WSS was reduced in Marfan patients in the left- the distal AAo and proximal DAo compared to healthy outer regions of the distal AAo and proximal aortic arch subjects (see top-right panel of Fig. 2). These differences and in the left-inner regions of the proximal DAo (see were statistically-significant on multivariate analysis after bottom row of Fig. 3). Regions of statistically-significant inclusion of sex, age, height, DBP, aortic root diameter differences in multivariate analysis are shown in the and aortic valve regurgitant fraction and maximum vel- right panel of Fig. 3. ocity as independent variables. This means that a reduc- Non-dilated Marfan patients presented limited regions tion in in-plane rotational flow is present in Marfan of altered axial or circumferential WSS in the proximal without clinically-significant aortic dilation. Conversely, AAo compared to HV (see Fig. 4). The reduction in SFRR was lower in non-dilated Marfan patients, thereby circumferential but not axial WSS was statistically- suggesting that the increase in such a flow alteration may significant in the left/inner regions of the proximal DAo partially result from dilation. on multivariate analysis. In univariate analysis in all Marfan patients, average Mean axial WSS in the left/left-inner region in the IRF over the ascending aorta, aortic arch and proximal proximal DAo was lower in MFS patients compared descending aorta was related to BSA (R = 0.28), max- with healthy subjects(0.315 vs 0.429 N/m2, respectively, imum velocity at the sinotubular junction (R = 0.270) p = 0.010), even after multivariate adjustment (p = and DAo PWV (R = -0.30) but not with age, sex, systolic 0.018). However, though similar, the difference with Guala et al. Journal of Cardiovascular Magnetic Resonance (2019) 21:63 Page 6 of 11 Fig. 2 Rotational flow characteristics. In-plane rotational flow (IRF) (top) and systolic flow reversal ratio (SFRR) (bottom) at the 20 analysis planes. Blue lines and box plots present data for healthy subjects, red regards all Marfan syndrome patients (left) while green reports data from non- dilated Marfan syndrome patients (right).* Statistically-significant (p < 0.05) difference between the groups after multivariate corrections healthy subjects was not statistically-significant (0.309 N/ (0.028 N/m2, p = 0.024) compared to healthy subjects , m2, p = 0.065) in non-dilated Marfan. Contour-averaged even after multivariate adjustments (p = 0.001 and p = circumferential WSS in the proximal DAo was strongly 0.042, respectively). related to local IRF (R = 0.805, p < 0.001) and was re- duced in the overall Marfan cohort (0.021 vs. 0.065 N/ Multivariate determinants of proximal DAo diameter m2, respectively. p < 0.001) and in the non-dilated group Univariate and multivariate correlates of DAo maximum diameter are described in Table 3. In multivariate ana- Table 2 univariate and multivariate linear regression analysis for lysis, local contour-averaged circumferential WSS (p = thoracic aorta mean IRF in Marfan patients 0.034) and axial WSS in the inner wall (p = 0.014) were Univariate Multivariate significantly and independently related to maximum p-value p-value B IC proximal DAo diameter after correction for age and BSA Age [years] 0.637 – – – (see Table 3). Of note, the performance of the multivari- BSA [m2] 0.020 0.047 0.235 [−0.129;17.528] ate model was very good, with an adjusted R2 of 54%. Sex [male] 0.110 – – – Discussion SBP [mmHg] 0.117 – – – This study analyzed blood flow and WSS patterns as DBP [mmHg] 0.438 – – – well as aortic stiffness by 4D flow CMR in the thoracic Aortic root z-score 0.203 – – – aorta of a large cohort of Marfan patients with and with- Vmax [cm/s] 0.020 0.050 0.231 [0.000; 0.138] out aortic dilation to identify potential early markers of AAo PWV [m/s] 0.165 – – – descending aorta disease. To our knowledge, this is the first study to quantitatively evaluate all these interrelated DAo PWV [m/s] 0.013 0.041 −0.232 [−0.875; −0.019] aspects in Marfarn patients. SBP, DBP: systolic and diastolic blood pressure, respectively. AAo represents ascending and DAo descending aorta, Vmax is the maximum through-plane Vortexes in the proximal DAo of unselected Marfan velocity at the sinotubular junction and PWV means pulse wave velocity adults were found to differ from those of healthy Guala et al. Journal of Cardiovascular Magnetic Resonance (2019) 21:63 Page 7 of 11 Fig. 3 WSS maps in healthy subjects and in Marfan patients. Axial (top) and circumferential (bottom) wall shear stress (WSS) in the ascending aorta, aortic arch and proximal descending aorta in healthy subjects (left) and in Marfan patients (center). (Right) Statistically-significance differences (p < 0.05) maps after multivariate corrections (red = healthy subjects higher, blue = Marfan higher) individuals. These vortexes were characterized by a large of the voxels included in IRF computation are located) reduction in in-plane rotational flow (IRF, the in-plane and outermost layers, where WSS is calculated, uniform. projection of helical flow) in the distal ascending aorta, This positive relationship had already been reported or at aortic arch and proximal DAo and a limited increase in least suggested by a number of studies [23–25], which through-plane vortexes (SFRR) located in dilation re- emphasized the role of helical flow-induced WSS to limit gions. Moreover, IRF but not SFRR was impaired in platelet activation, atherogenic lipid adhesion and energy Marfan patients without aortic root or DAo dilation (see dissipation [26, 27]. Finally, in multivariate analysis cor- Additional file 2: Video 1). Similar results were obtained rected for age and BSA, both local circumferential and for wall shear stress, the circumferential, but not axial, axial WSS in the proximal DAo were significantly and component of which was reduced even in non-dilated independently related to local diameter. patients. A marked, positive relationship between in-plane Vortexes in the proximal DAo of adolescent Marfan rotational flow and circumferential WSS was observed, as patients were recently identified by semi-qualitative visual expected. Indeed, viscous and inertial forces tend to inspection of 4D flow CMR studies [6–8]. However, none render the velocity field between innermost (where most of those studies differentiated between rotation axis Guala et al. Journal of Cardiovascular Magnetic Resonance (2019) 21:63 Page 8 of 11 Fig. 4 WSS maps in healthy subjects and in non-dilated Marfan patients Axial (top) and circumferential (bottom) wall shear stress (WSS) in the ascending aorta, aortic arch and proximal descending aorta in healthy subjects (left) and in Marfan patients without aortic dilation (center). (Right) Statistically-significance differences (p < 0.05) maps after multivariate corrections (red = healthy subjectshigher, blue = Marfan higher) directions [6–8]. Interestingly, the present study found in- To appreciate the significance of this finding, it is import- creased systolic flow reversal ratio (SFRR) to be absent in ant to consider the physiologic role of helical flow. Indeed, non-dilated Marfan patients, thereby indicating that it is thought to limit the separation of flow from the arter- through-plane vortexes might be a consequence of local ial wall when flowing through regions with sudden geo- dilation. On the other hand, in-plane vortexes, as identi- metric or mechanical heterogeneity (such as bifurcations), fied through the computation of in-plane rotational flow, thereby limiting energy dissipation [23–25, 28]. In other were found to be reduced in the distal AAo and aortic words, a coherent helical flow pattern results from evolu- arch. This concurs with a quantitative study reporting tion aimed at obtaining more efficient blood flow [24, 25, reduced helical flow in the AAo in a small population of 29]. In light of this, impaired IRF, a proxy of helical flow, adult Marfan patients [5]. Our data further showed the in Marfan patients could effectively be seen as a patho- reduction in IRF to be highly related to a reduction in logic characteristic. Regarding the origin of impaired hel- circumferential WSS, occur even in non-dilated Marfan ical flow in Marfan patients, our data revealed an patients and be independently related to aortic stiffness. independent inverse relationship with descending aorta Guala et al. Journal of Cardiovascular Magnetic Resonance (2019) 21:63 Page 9 of 11 Table 3 univariate and multivariate linear regression analysis for proximal DAo maximum diameter in MFS patients Univariate Multivariate p-value p-value B IC Age [years] < 0.001 < 0.001 0.583 [0.136; 0.247] BSA [m2] 0.020 < 0.001 0.416 [4.815;11.326] SBP [mmHg] 0.007 – – – DBP [mmHg] 0.421 – – – Aortic root diameter [mm] 0.048 – – – AAo PWV [m/s] 0.421 – – – DAo PWV [m/s] 0.044 – – – Circ. WSS14 0.021 0.034 −0.182 [−37.4; −1.5] Proximal DAo inner axial WSS 0.019 0.014 −0.218 [−9.2; −1.1] SBP, DBP: systolic and diastolic blood pressure, respectively. AAo represents ascending and DAo descending aorta, PWV means pulse wave velocity and WSS wall shear stress stiffness and not with aortic root z-score and age, thereby as IRF is computed over the whole cross-section, the suggesting a role for aortic stiffness in the creation of this topology of local secondary flow structures could not be abnormal flow feature. Of note, reduced IRF highlights a depicted. The 4D flow studies were acquired without difference with respect to bicuspid aortic valve patients respiratory gating. This should not imply substantial who present abnormally elevated IRF [13, 15]. differences in the descending aorta, where respiratory Interestingly, helical flow rotated counterclockwise in motion is limited [31], especially during tidal breathing the middle of the proximal DAo in Marfan patients, the [32], as in the present investigation. The cross-sectional site of maximum diameter. Counterclockwise rotational nature of the study implies the impossibility of investigat- flow has been suggested as a more severe flow alteration ing causal relationship between variables. The capacity of in bicuspid aortic valve patients [30]. IRF and circumferential WSS to predict outcomes should WSS maps revealed axial WSS to be reduced in the thus be assessed in longitudinal studies. dilation-affected regions. However, comparing non- dilated Marfan patients with healthy subjects showed a Conclusions limited number of regions with statistically-significant Impaired in-plane rotational flow and circumferential differences in axial WSS. By contrast, circumferential wall shear stress are present in Marfan patients regard- WSS was reduced in both dilated and non-dilated Mar- less of aortic dilation. Reduced axial and circumferential fan patients and may thus be an early marker of disease. wall shear stress in the proximal descending aorta are The reduction in axial and circumferential WSS seen in independently related to local diameter beyond demo- the present study supports previous findings in a much graphics and classic clinical factors. smaller Marfarn population [5]. Multivariate analysis showed circumferential and axial WSS to be independent correlates of proximal DAo Additional file diameter beyond age, BSA and regional stiffness. This result adds to previous findings [6] with respect to the Additional file 1: Numerical results included in Fig. 2.(DOCX 27 kb) vectorial nature of WSS, and further suggests that local Additional file 2: Representative video comparing a dilated Marfan patient (right), a non-dilated Marfan patient (center) and a healthy hemodynamics may be superior to local stiffness in the controls (left). (MP4 8940 kb) etiology of DAo dilation. Despite the need for longitu- dinal studies to demonstrate a potential causative role, Abbreviations these data suggest that the WSS measurement may be 3D: Three-dimensional; 4D flow CMR: Time-resolved three-dimensional important in the clinical management of Marfarn pa- phase-contrast cardiac magnetic resonance imaging; AAo: Ascending aorta; tients and deserve further longitudinal studies. BSA: Body surface area; bSSFP: balanced steady state free precession; CMR: Cardiovascular magnetic resonance; DAo: Descending aorta; DBP: Diastolic blood pressure; ECG: Electrocardiogram; IRF: In-plane rotational flow ; MRA: Magnetic resonance angiography; PC: Phase contrast; PWV: Pulse Limitations wave velocity; SBP: Systolic blood pressure; SFRR: Systolic flow reversal ratio; STJ: Sinotubular junction; VENC: Velocity encoding; WSS: Wall shear stress IRF and WSS were computed by averaging the flow field of three time frames around peak systole [15]. This Acknowledgments method permits noise the reduction but can result in We are grateful to Christine O’Hara for English revision and to Martina extremely rapid fluctuations being missed. Furthermore, Strisciullo for video editing. Guala et al. Journal of Cardiovascular Magnetic Resonance (2019) 21:63 Page 10 of 11 Authors’ contributions 10. Johnson KM, Lum DP, Turski PA, Block WF, Mistretta CA, Wieben O. AG, T-TG: design of the work, image analysis, statistical analysis, interpretation Improved 3D phase contrast MRI with off-resonance corrected dual Echo of data, draft. JKM, WO: sequence development and optimization. GC, VF, G- VIPR. Magn Reson Med. 2009;60(6):1329–36. https://doi.org/10.1002/mrm.21 GL, GL, G-AT: patients selection, image collection, interpretation of data. D-SL, 763.Improved. R-MA: image analysis, interpretation of data. S.A.A.: statistical analysis, inter- 11. Yushkevich PA, Piven J, Hazlett HC, et al. User-guided 3D active contour pretation of data. All authors read and approved the final manuscript. segmentation of anatomical structures: significantly improved efficiency and reliability. Neuroimage. 2006;31(3):1116–28. https://doi.org/10.1016/j. Funding neuroimage.2006.01.015. This study has been funded by Instituto de Salud Carlos III through the 12. Hess AT, Bissell MM, Glaze SJ, Pitcher A, Myerson SG, Neubauer S, et al. project PI14/0106 (co-founded by European Regional Development Fund), La Evaluation of circulation, Γ, as a quantifying metric in 4D flow MRI. J Marató de TV3 (project number 20151330), by Ministerio de Economía y Cardiovasc Magn Reson. 2013;15(Suppl 1):E36. https://doi.org/10.11 Competitividad through Retos-Colaboración 2016 (RTC-2016-5152-1). Guala 86/1532-429X-15-S1-E36. A. has received funding from the European Union Seventh Framework 13. Dux-Santoy L, Guala A, Teixidó-Turà G, Ruiz-Muñoz A, Maldonado G, Villalva Programme FP7/People under grant agreement n° 267128. N, et al. Increased rotational flow in the proximal aortic arch is associated with its dilation in bicuspid aortic valve disease. Eur Hear J - Cardiovasc Imaging. 2019;34:1–11. Availability of data and materials 14. Bensalah MZ, Bollache E, Kachenoura N, et al. Geometry is a major The data that support the findings of this study are available from the determinant of flow reversal in proximal aorta. Am J Physiol Hear Circ corresponding author upon reasonable request. Physiol. 2014;306:1408–16. https://doi.org/10.1152/ajpheart.00647.2013. 15. Rodríguez-Palomares JF, Dux-Santoy L, Guala A, et al. Aortic flow patterns Ethics approval and consent to participate and wall shear stress maps by 4D-flow MRI in the assessment of aortic The study was approved by the local ethics committee and written informed dilatation in bicuspid aortic valve. J Cardiovasc Magn Reson. 2018;20(28). consent was obtained from all participants. https://doi.org/10.1186/s12968-018-0451-1. 16. 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