Comparison of Different Thoracic Aortic Wall Characteristics for Assessment of Disease Activity in Takayasu Arteritis: A Quantitative Study with 3.0 T Magnetic Resonance Imaging

Background : Determination of disease activity in Takayasu arteritis (TAK) is crucial for clinical management but challenging. The value of different magnetic resonance imaging (MRI) characteristics for the assessment of disease activity remains unclear. This study investigated the imaging findings of the thoracic aortic wall and elasticity by using a comprehensive 3.0 T MRI protocol. Methods : We prospectively enrolled 52 consecutive TAK patients. TAK activity was recorded according to the ITAS2010. All the patients underwent thoracic aortic MRI. The luminal morphology of the thoracic aorta and its main branches were quantitatively evaluated using a contrast-enhanced magnetic resonance angiography (MRA) sequence. The maximum wall thickness of the thoracic aorta, postcontrast enhancement ratio, and aortic wall edema were analyzed in each patient through pre-and post-enhanced T1-weighted and T2-weighted imaging. Pulse-wave velocity (PWV) of the thoracic aorta was calculated using a four-dimensional flow technique. Results : The majority of the 52 patients had type V disease (34.62%, 18/52). Among all the MRI indicators of the thoracic aorta, the area under the curve was the largest for the maximal wall thickness (0.804, 95% confidence interval [CI] = 0.667–0.941). The maximal wall thickness (93.33%, 95% CI = 68.1%–99.8%) exhibited the highest sensitivity with a cutoff value of 3.12 mm. Wall edema (84.00%, 95% CI = 63.9%–95.5%) presented the highest specificity. A positive correlation was noted between PWV and patients’ age (r = 0.54, p < 0.001), disease duration (r = 0.52, p < 0.001), and the maximum wall thickness (r = 0.45, p = 0.001). Conclusions : MRI enabled the comprehensive assessment of aortic wall morphology and functional markers for TAK disease activity. Aortic maximal wall thickness was the most accurate indicator of TAK activity. The early phase was superior to the delay phase for aortic wall enhancement analysis for assessing TAK activity.


Introduction
Takayasu arteritis (TAK) is a form of large-vessel vasculitis of unknown etiology.Precise examination of disease activity in patients with TAK is crucial for management.Disease remission should be achieved and maintained prior to and after surgery [1].
Evaluation of disease activity in patients with TAK remains clinically challenging.The National Institute of Health activity criteria [2] and the Birmingham Vasculitis Activity Score (BVAS) [3] have been traditionally used to examine disease activity.In the past decade, a new Indian Takayasu clinical activity score (ITAS2010) was developed for assessing TAK activity on the basis of clinical symptoms and laboratory findings determined using the BVAS [4].However, inconsistency was noted in a substantial proportion of patients with TAK in terms of their active symptoms, serum acute phase reactant levels, and radiological inflammation.Hence, the accuracy of the clinical activity score remains suboptimal.
Various imaging modalities including ultrasonography, computed tomography angiography (CTA), magnetic resonance imaging (MRI), and 18 F-fluorodeoxyglucosepositron emission tomography (FDG-PET) have been employed to examine disease activity.These modalities can distinguish disease activity from damage.Ultrasound, CTA, and MRI can accurately evaluate the morphology of the arterial wall and lumen.By contrast, ultrasonography is mainly used for evaluating peripheral arteries, especially the carotid artery in patients with TAK.The maximum intima-media thickness determined through ultrasonography is a favorable indicator of TAK activity [5].Obvious contrast-enhanced ultrasound vascularization reflects TAK activity [6].In addition, arterial wall thickness and enhancement and characteristic CTA findings (e.g., low-attenuation ring and aortic positive remodeling) can indicate TAK activity [7].Uptake of FDG-PET exhibited the highest sensitivity for determining TAK activity but lacked specificity [8,9].Furthermore, arterial wall edema, which can be observed through T2-weighted imaging (T2WI) and diffused weighted imaging (DWI) with MRI, is a specific indicator of TAK activity [10,11].The four-dimensional flow technique with MRI can be employed to evaluate hemodynamics and elasticity.Pulse-wave velocity (PWV) is associated with TAK activity [12,13].However, the value of different MRI findings for the examination of disease activity remains unclear.Moreover, a standard MRI scan protocol for clinical use is not available.Furthermore, studies using 3.0 T MRI are limited.This study investigated the imaging findings of the thoracic aortic wall and elasticity by using a comprehensive 3.0 T MRI protocol.The clinical value of MRI findings for determining TAK activity was compared using ITAS2010 clinical activity as the reference standard.

Study Participants
This prospective single-center study was approved by our institutional review board.Written informed consent was obtained from each participant.Between June 2014 and December 2018, we enrolled 52 consecutive patients, including 18 first diagnosed and 34 revisited patients with TAK in this study.The definitive diagnosis of TAK was based on the 1990 American College of Rheumatology criteria [14].TAK activity was examined according to the ITAS2010 [4].All patients had been treated with glucocorticoids and immunosuppressive agents.High dose glucocorticoid therapy (40-60 mg/day) was used for induction of remission in the active TAK patients.Once remission occurred, the glucocorticoid dose was tailored to a target dose of 15-20 mg/day within 2-3 months and to ≤10 mg/day after 1 year.According to clinical data and routine imaging findings, including those of ultrasonography, CTA, and MRI, the patients with TAK were classified into Types I to V [15].We excluded nine patients because of contraindications to MRI (n = 3), contraindications to contrast media (n = 2), and poor image quality due to arrhythmia (n = 3) and poor holding of breath (n = 1).Fig. 1 depicts the study flowchart.

MRI
All MRI examinations were performed using a 3.0 T MRI scanner (Verio, Siemens, Erlangen, Germany) equipped with a 32-channel surface-phased-array coil.The coil was placed beneath the mandible bone encompassing the whole thorax.As shown in Fig. 2, a 30-min comprehensive aortic MRI protocol was designed for the patients with TAK including dark-blood T2WI; contrast-enhanced magnetic resonance angiography (CE-MRA); pre, early, and delayed gadolinium enhanced T1-weighted imaging (T1WI); and 4D flow sequence.
A breath-holding 3D gradient-echo (fast low-angle shot, FLASH) sequence (TE/TR = 1.1 ms/3.1 ms, FOV = 38.0 × 30.8 cm 2 , matrix = 384 × 281, slice thickness = 1.2 mm, and 104 slices per slab) was used to acquire CE-MRA in coronal orientation before and after administering the contrast medium.K-space was filled by adopting the central first approach.A postcontrast scan was performed after the intravenous administration of gadopentetate dimeglumine (Magnevist, Bayer, 0.2 mmol/kg body weight, 2 mL/s) with 30 mL of saline flush at the same injection rate.The optimal acquisition time was determined using a bolustracking sequence.
The 4D flow sequence covered the whole thoracic aorta with oblique coronal orientation in prospectively ECG-gated and navigation techniques (temporal resolution = 47.2 ms, slice thickness = 1.8 mm, TE/TR = 2.8 ms/47.2ms, FOV = 34.0× 25.5 cm 2 , and matrix = 192 × 115).Subsequently, a two-dimensional phase-contrast cine MRI was performed to acquire optimal velocity encoding (VENC) before the 4D flow sequence.The VENC value was 100-200 cm/s, which was determined using the maximum flow velocity measured in the thoracic aortic lumen.The acquisition time for the 4D flow sequence was 6-9 min.

Image Analysis
All the acquired images were evaluated by a radiologist (N.Z.) with 11 years of experience in cardiovascular imaging.The radiologist was blinded to clinical findings.

Aortic MRA Analysis
Image postprocessing and evaluation were performed on a Siemens workstation (SyngoMMWP VE40A, Siemens Med Service Software, Erlangen, Germany).Stenosis and dilation of different arterial segments were evaluated by comparing the diameter of the diseased segment with the luminal diameter of the adjacent normal-caliber arterial segment.Pathological entities of each arterial segment were classified as stenosis, occlusion, and dilatation.Ten arterial segments were evaluated for each patient including bilateral subclavian arteries, brachiocephalic trunk (BT), bilat-  eral common carotid arteries (CA), bilateral vertebral arteries (VA), ascending aorta (AA), aortic arch, and descending aorta (DA).

Aortic Wall Analysis
Image postprocessing and evaluation were performed on a Siemens workstation (SyngoMMWP VE40A, Siemens Med Service Software).The following parameters were evaluated: • Maximum wall thickness of the thoracic aorta: The aortic wall thickness was examined at the thickest site in thoracic aorta by using dark-blood T2WI.
• Postcontrast enhancement ratio: Regions of interest (ROIs) with a size of 5 to 12 pixels were set on the thickest aortic wall in pre-, early, and delay enhanced T1WI, avoiding the adjacent intra-and extra-luminal tissue and artifact.Additional ROIs were designated on the left erector spinae muscle at the same slice.The signal intensity ratio (SIR) and enhanced SIR (ESIR) of the aortic wall to the adjacent muscle were calculated as follows.
where SI A is the SI of the thickest aortic wall on enhanced one mask with a threshold and the manual modification of the flow region.The centerline of the aorta was determined using the 2-point or multipoint method.Aortic plane selection: An appropriate plane of the aorta perpendicular to the centerline was selected and the contour of the aorta was manually modified.Hemodynamic analysis: Hemodynamic parameters (e.g., flow and velocity) were automatically acquired through the defined planes.PWV was automatically calculated using the phase shifting of profiles and the length between two planes along the centerline.
T1WI and SI M is the SI of the left erector spinae muscle in the same slice on enhanced T1WI.
where SI A is the SI of the thickest aortic wall on enhanced T1WI; SI Apre is the SI on the thickest aortic wall in preenhanced T1WI; SI M is the SI on the left erector spinae muscle in the same slice on enhanced T1WI; and SI M pre is the SI on the left erector spinae muscle in the same slice on pre-enhanced T1WI.
• Aortic wall edema: The presence of aortic wall edema was considered when a high SI was noted in the thickened aortic wall on dark-blood T2WI.

PWV Analysis
The 4D flow data were analyzed using a specialized module from CVI42 software (V5.13.7,Circle, Calgary, AB, Canada) [16].After offset correction and antialiasing during preprocessing, the entire thoracic aorta was segmented and centerline extraction was semiautomatically performed through manual modification.Subsequently, for quantitative analysis, aortic 4D flow data were acquired from the aortic root to the distal descending aorta.A semiautomatic contour detection algorithm with manual verification was used to identify the aortic plane perpendicular to the aortic centerline.PWV was automatically calculated for each patient after placing two planes at the aortic root and distal descending aorta, respectively (Fig. 3).

Statistical Analysis
Statistical analysis was performed using MedCalc statistical software, version 20.019 (MedCalc Software Ltd, Ostend, Belgium).Continuous variables are expressed as the mean ± standard error or a median with 25%-75% interquartile range.Categorical variables are expressed as absolute numbers and percentages.Distribution of the normality of continuous variables was examined using the Kolmogorov-Smirnov test.Normally distributed variables were compared using the independent sample t test.Nonnormally distributed variables were compared using the Mann-Whitney U test for the two groups.Categorical variables were compared using the chi-squared test.The correlation of PWV with age, disease duration, maximum wall thickness of the thoracic aorta, and delay ESIR was analyzed using Pearson's correlation test.Receiver-operating characteristic (ROC) curve analysis was performed to compare the diagnostic performance of the maximum wall thickness of the thoracic aorta, aortic wall edema, early ESIR, the PWV of the thoracic aorta, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP).The best cutoff values were determined using Youden's index.A p value of <0.05 was considered statistically significant.

Study Population Characteristics
A total of 52 patients were enrolled in this study including 23 and 29 patients with active and inactive TAK, respectively, according to ITAS2010/ITAS.A.The majority of the patients were classified as type V (34.62%, 18/52),

Thoracic Aortic MRA
A total of 520 arterial segments were evaluated in the 52 patients.Arterial pathologies were noted in 193 segments (96 and 97 segments in the active and inactive groups, respectively), including 123 stenosed, 51 occlusive, and 19 dilated segments.The left subclavian artery (44/52, 84.62%) was the most commonly involved segment, followed by the right subclavian artery (38/52, 73.08%) and the left common carotid artery (33/52, 63.46%).Arterial dilation was more common in the aorta (12 segments) including 7 segments of the ascending aorta, 2 segments of the aortic arch, and 3 segments of the descending aorta.Table 2 presents the details of these pathologies.

Aortic Wall Imaging
The maximum wall thickness of the thoracic aorta was significantly larger in the active group (3.89 ± 1.50 mm vs. 3.00 ± 1.04 mm, p = 0.009; Table 3).Compared with the inactive group, more patients in the active group exhibited a high SI at the aortic wall (56.5% [13/23] vs. 17.2% [5/29], p = 0.003) on T2WI images, indicating the presence of aortic wall edema.In the early enhanced scan, the postcontrast enhancement ratio was significantly higher in the active group when weighted with ESIR (2.63 ± 2.14 vs. 1.11 ± 1.04, p = 0.013).Although aortic SIR and ESIR were higher in the active TAK group in delay enhanced images, no significant difference was observed between the active and inactive TAK groups.Fig. 4 presents the findings of a patient with active TAK.

ROC Analysis
Among all the MRI indicators of the thoracic aorta, the area under the curve (AUC) was the largest for the maximal wall thickness (0.804, 95% CI = 0.667-0.941).According to the ROC curve analysis of these MRI indicators, the cutoff values of the maximal wall thickness, early enhanced ESIR, and PWV were 3.12 mm, 1.13, and 6.4 m/s, respectively.On the basis of these cutoff values, the maximal wall thickness exhibited the highest sensitivity for the determination of active TAK (93.33%, 95% CI = 68.1%-99.8%),whereas wall edema demonstrated the highest specificity (84.00%, 95% CI = 63.9%-95.5%;Table 4).

Discussion
In this study, we used a comprehensive MRI protocol of the thoracic aorta to determine the morphological and functional characteristics of the aortic wall.We examined whether these characteristics can be used to assess disease activity in 52 patients with TAK.The maximal wall thickness was the most favorable indicator for determining TAK activity with the highest sensitivity.Aortic wall edema can be used as a specific marker to detect TAK activity with high specificity.Compared with delay enhancement, early-enhanced ESIR was a better indicator of TAK activity.Furthermore, by using the 4D flow technique, aortic PWV could be determined to detect active TAK with high sensitivity.
Accurate assessment of TAK activity is crucial for clinical management but remains challenging with the current approaches.Studies have investigated TAK activity by using different imaging modalities.Ultrasound is a convenient and cheap imaging method that is the most widely used in clinical practice to evaluate the peripheral arteries of patients with TAK.Characteristic thickening of the carotid arterial wall is an accurate diagnostic clue for TAK disease.The maximum intima-media thickness and contrastenhanced ultrasound can be reliable indicators for detecting disease activity.However, the difficulty of aortic wall assessment limits the usage of ultrasound in patients with TAK with aorta involvement.CTA allows the visualization of the lumen and wall of variable arteries in the whole body.The high spatial resolution of CTA enables the quantitative assessment of morphological characteristics.Arterial wall thickness, wall enhancement, low-attenuation ring, and aortic positive remodeling are the indicators of TAK activity.Use of ionizing radiation and iodinated contrast agents raise concerns in patients with TAK with renal dysfunction or those requiring regular follow-up imaging.FDG-PET is the most sensitive imaging modality for detecting active local inflammatory changes in the aortic and peripheral arterial wall [8,9].However, the use of FDG-PET is hindered by its high cost, ionizing radiation, low specificity, and low spatial resolution.
Because of its ability to accurately examine soft tissue characteristics and the availability of a range of dedicated sequences, MRI has been widely used in clinical practice for the assessment of TAK activity [8].Similar to CTA, MRI enables accurate whole-body vascular characterization [17].Stenosis, occlusion, and dilation of systemic ar-teries can be quantitatively evaluated through MRA.Information on the involved arterial site, extent, and degree can be obtained with high reproducibility.With the development of the MRI technique, 2D or 3D multi-weighted vessel wall imaging can be used for examining the whole-body vascular structure.Thus, MRI is useful for early diagnosis, activity assessment, and relapse identification in patients with TAK.Functional evaluation of the aorta, including its hemodynamic and elasticity, can provide additional information regarding activity and prognosis.Hence, a comprehensive MRI protocol was used in this study for examining patients with TAK.
TAK is a form of large-vessel arteritis including the aorta, aortic primary branches, coronary arteries, and pulmonary arteries.Active arterial lesions can be solitary, diffuse, or multiple.Thus, for accurate TAK activity assessment, arteries in the whole body should be evaluated.Difficulty in examining all diseased arterial segments can lead  to a decreased sensitivity of TAK activity assessment.Because of the time-consuming nature and magnetic field inhomogeneity of the 3.0 T system, only the thoracic aortic wall was evaluated for determining the clinical activity of the patients with TAK in this study.Although the majority of the patients in the cohort had type V disease (34.62%, 18/52) with the simultaneous involvement of the carotid arteries, thoracic aorta, and abdominal aorta, the largest AUC of MRI indicators reached 0.804 (95% CI = 0.667-0.941) in the maximal thoracic aortic wall thickness.When considering the whole aorta, in a CTA study [7], the AUC of the maximal aortic wall thickness for determining TAK activity reached 0.906 (95% CI = 0.850-0.946).In addition to the aorta, carotid intima-media thickness measured through ultrasound and 18 F-FDG uptake of the pulmonary artery in FDG-PET exhibited a satisfactory correlation with disease activity [18,19].
Aortic PWV evaluated using the 4D flow technique was a potential indicator of TAK activity and prognosis.
Brachial-ankle and carotid-femoral PWV were correlated with TAK disease activity [12,13].Similar to arteriosclerosis, brachial-ankle PWV levels in patients with TAK were associated with major adverse cardiac events [31].Because stenotic and occlusive lesions usually occur in the peripheral arteries in patients with TAK, aortic PWV derived from MRI can reflect arterial elastic function more accurately compared with brachial-ankle or carotid-femoral PWV.In this study, thoracic aortic PWV was significantly increased in the active TAK group (10.45 ± 5.11 m/s vs. 7.20 ± 3.66 m/s, p = 0.016).With a cutoff value of 6.4 m/s, PWV could identify active TAK with an AUC of 0.723 (95% CI = 0.566-0.879),a sensitivity of 86.67% (95% CI = 59.5%-98.3%),and a specificity of 56.00% (95% CI = 34.9%-75.6%).Except for age and the disease duration, a positive correlation was observed between PWV and the maximum wall thickness of the thoracic aorta.By contrast, a negative correlation was noted between PWV and delay enhanced ESIR.Wall thickening and fibrosis might be pathological factors affecting arterial elastic function in patients with TAK.

Limitations
This study has several limitations.First, this was a single-center study.The sample size was relatively small.Second, no follow-up MRI images were available for this cohort.Future studies with large sample sizes and followup data are warranted.Third, only the thoracic aorta was evaluated in this study.Whole-body MRI including the whole aorta, carotid artery, and pulmonary artery might determine TAK disease activity more accurately.

Conclusions
MRI enables the comprehensive evaluation of the morphological and functional features of the aortic wall that can be used for determining TAK disease activity.Among all the MRI parameters, aortic maximal wall thickness was the most accurate indicator of TAK activity.The early phase was superior to the delay phase for aortic wall enhancement analysis to determine TAK activity.Except for age and the disease duration, aortic wall thickening and fibrosis can be pathological factors for affecting arterial elastic function in patients with TAK.

Fig. 1 .
Fig. 1.Flowchart for the selection and analysis of patients with TAK (n = 52).After excluding 9 patients, a total of 52 cases with TAK were included in the analysis.

Fig. 2 .
Fig. 2. Comprehensive aortic MRI protocol for patients with TAK.Pre-enhanced T1WI and dark-blood T2WI with transversal orientation performed after localization.CE-MRA was performed using the bolus-tracking sequence after contrast injection.Early and late enhanced T1WI were performed 1 and 15 min after contrast injection, respectively, with the repetition of pre-enhanced T1WI.Within the delayed period, a 4D flow sequence was performed for a duration of 6-9 min.

Fig. 3 .
Fig. 3. 4D flow MRI analysis workflow.During preprocessing, the vessel area was masked for offset correction.Then, an antialiasing algorithm was used if the aliasing artifact existed in the flow region.Segmentation and centerline extraction were performed to define

Fig. 4 .
Fig. 4. MRI findings of a 32-year-old female patient with active TAK with an ITAS2010 score of 10, an ESR of 14 mm/h, and a CRP level of 32.16 mg/L.(A,B) CE-MRA showed occlusive lesions at the LSCA, RCA, and right renal artery.Significant stenosis was observed at the RSCA.(C) T2WI showed a thickened descending aortic wall with obvious edema.The thickness of the descending aortic wall was 4.65 mm.(D-F) Early and delay enhancement of the thickened descending aortic wall were observed with an early SIR of 2.20, an early ESIR of 5.46, a delay SIR of 2.95, and a delay ESIR of 6.84.
[10] demonstrated that low b-value DWI was superior to T2WI in identifying aortic wall inflammation in patients with active TAK.The findings of TAK activity assessment performed using arterial wall contrast enhancement have been inconsistent.Most of the researchers have indicated that aortic wall contrast enhancement on MRI findings is suggestive of active TAK[10,21,22,28,29].Kato et al.[26] reported that 30-min late gadolinium enhancement (LGE) with the Look-Locker inversion-recovery sequence was useful for the detection of arterial wall involvement.However, TAK activity could not be determined through LGE.The inconsistency in the results may be due to the use of varying delay scan times, imaging techniques, and definitions of active TAK.Choe et al.[28] observed the early (delay within 5 min), intermediate (delay of 5-10 min), and late (delay of 10-20 min) contrast enhancement patterns of the aortic wall in patients with TAK by using spinecho T1WI images.Increased enhancement was noted in patients with active TAK on early, intermediate, and late enhanced scans.However, only the early contrast enhancement of the aortic wall was well-correlated with the ESR (r = 0.78, p < 0.005) and CRP (r = 0.63, p < 0.005).In this study, we performed a post contrast-enhanced scan at 1 and 15 min by using the VIBE technique.Compared with the inactive TAK group, the active TAK group exhibited a significantly increased ESIR on early enhanced images (2.63 ± 2.14 vs. 1.11 ± 1.04, p = 0.013).With a cutoff value of 1.13, early enhanced ESIR could identify active TAK with an AUC of 0.723 (95% CI = 0.565-0.880),a sensitivity of 66.67% (95% CI = 38.4%-88.2%