Clinical characteristics, imaging phenotypes and events free survival in hypertensive Takayasu arteritis population

Hypertension occurred in 30–80% of Takayasu arteritis (TAK) patients around the world and the occurrence of hypertension might worsen the disease prognosis. This study aimed to investigate the clinical characteristics and imaging phenotypes, as well as their associations with events free survival (EFS) in hypertensive TAK population. This current research was based on a prospectively on-going observational cohort-the East China Takayasu Arteritis (ECTA) cohort, centered in Zhongshan Hospital, Fudan University. Totally, 204 hypertensive TAK patients were enrolled between January 2013 and December 2019. Clinical characteristics and imaging phenotypes of each case were evaluated and their associations with the EFS by the end of August 30, 2020 were analyzed. glomerular ltration SD, standard deviations; interquartile range; HR, ESR, rate.


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Background Takayasu arteritis (TAK) is a chronic in ammatory large-vessel vasculitis that primarily affects the aorta and its main branches [1,2,3]. Hypertension is a particularly important complication in patients with TAK [4,5,6]. According to previous reports, hypertension occurred in 33-83% of patients with TAK from different areas of the world, with younger age of disease onset [7][8][9][10]. The occurrence of hypertension could severely worsen TAK prognosis and may be a signi cant prognostic predictor of outcomes [11].
Furthermore, uncontrolled blood pressure in hypertensive TAK patients was associated with a higher ve years all-cause mortality risk than that in the healthy population, despite effective control of disease activity [12,13]. Thus, comprehensive understanding of the disease characteristics of hypertensive TAK is very essential.
To our knowledge, few studies have focused on hypertension in the TAK population up to date. In a previous research, we reported that in patients with TAK-related renal artery stenosis, the prevalence of hypertension was up to 60%, with 30% refractory hypertensive cases [14]. Except renal artery stenosis, the involvement of abdominal aorta, as well as severe aortic regurgitation (AR) also could cause hypertension in TAK [15,16,17]. Nevertheless, data describing whether there are speci c imaging features in hypertensive TAK patients as well as the associations with disease prognosis were still lacking.
Thus, this study was designed to investigate the clinical characteristics and speci c imaging phenotypes of TAK patients with hypertension and to point out the associations of the clinical characteristics and imaging phenotypes with the events free survival (EFS).

Study design and subjects
The present study was based on a prospectively on-going observational cohort-the East China Takayasu Arteritis (ECTA) cohort, centered in Zhongshan Hospital, Fudan University, Shanghai, China. All patients enrolled into the ECTA cohort had a con rmed diagnosis of TAK based on the 1990 American College of Rheumatology (ACR) criteria [18]. The demographic, clinical, laboratory, and treatment data were collected at baseline and each visit. The follow-up frequency was once a month in the active phase and once every 3 months in the remission phase. Disease activity was assessed using the National Institutes of Health (NIH) criteria [19]. The clinical data of all enrolled patients were recorded and stored in a uni ed electronic database (REDCap database system, https://redcap.zs-hospital.sh.cn).
In all, 204 TAK patients with hypertension, were enrolled in to the current research from the ECTA cohort between January 2013 and December 2019. Clinical characteristics and imaging features of each case were evaluated by professional rheumatologists. The main outcome of the investigation was the EFS by the end of August 30, 2020 (Fig. 1). Associations of the clinical and imaging features with the EFS were analyzed. The study was performed in accordance with the tenets of the Helsinki Declaration and its amendments. The study protocol was approved by the Ethics Review Board of Zhongshan Hospital (B2013-115 (3)). Written informed consent was obtained from all patients.

Blood pressure measurement
Upper-limb blood pressure was measured in all patients. Blood pressure measurement of the four limbs, and ankle brachial index (ABI) was performed in 92/204 (45.1%) patients by using a noninvasive blood pressure monitor (BP-203RPEIII, Omron Healthcare Co., Ltd., Tokyo, Japan). For those without subclavian artery involvement, the reading from the arm with the higher value was used as the reference measurement. For patients with unilateral subclavian artery involvement, the reading from the unaffected side was analyzed, while for those with bilateral subclavian artery involvement, higher values of blood pressure of the lower limbs were used for analysis.
Classi cation of hypertensive severity and blood pressure control status The severity of hypertension was classi ed as previously reported [20]: (i) mild: a brachial pressure of 140-159 mmHg systolic or 90-99 mmHg diastolic; (ii) moderate: a brachial pressure of 160-179 mmHg systolic or 100-109 mmHg diastolic; and (iii) severe: a brachial pressure of ≥ 180 mmHg systolic or ≥ 110 mmHg diastolic.
Blood pressure control status was classi ed as: (i) controlled: systolic blood pressure (SBP) < 140 mmHg and diastolic blood pressure (DBP) < 90 mmHg; (ii) improved: SBP ≥ 140 mmHg, but decreased by ≥ 20 mmHg and/or DBP ≥ 90 mmHg, but decreased by ≥ 10 mmHg; and (iii) failure: failed meeting the abovede ned criteria. Refractory hypertension was de ned as a brachial pressure ≥ 160 mmHg systolic or ≥ 90 mmHg diastolic pressure despite maximal doses of three antihypertensive drugs for at least one month [14,21].

Imaging measurements
Imaging assessments, mainly the whole-body enhanced magnetic resonance angiography (MRA) or computed tomography angiography (CTA) were performed at the time of enrollment. Angiography ndings were classi ed according to the classi cation by Numano et al. in 1996 [22].
Diagnosis of AR was con rmed by echocardiography according to the guideline of the American Society of Echocardiography [23]. The severity of AR was evaluated by echocardiography as previously described [24,25].

Outcomes
Patients, who completed at least 6 months follow-up, were included in the outcome analysis. The occurrence of any events during the follow-up included: (i) renal insu ciency including new occurrence, persistent insu ciency (≥ 6 months) or deterioration of renal function (≥ 20% increase in creatinine concentration or ≥ 20% decrease in glomerular ltration rate (GFR); (ii) persistent refractory hypertension (≥ 6 months) or malignant hypertension; (iii) congestive heart failure including new occurrence or deterioration of heart function; (iv) new occurrence of cerebrovascular events; (v) arterial dissection or rupture of aneurysms; or (vi) TAK-related death (e.g., death caused by severe arterial stenosis or aortic dissection).

Statistical analysis
Categorical variables were summarized as counts and percentages and were compared using chi-square or Kruskal-Wallis tests. Continuous variables are presented as means ± standard deviations (SD) or as medians with interquartile range (IQR), depending on the normality of distribution, and were compared using Student's t-tests, Wilcoxon tests, or one-way ANOVA. For variables with signi cant differences among three or more groups, pair-wise comparisons were further performed using Student's t-tests, Wilcoxon tests, or chi-square tests.
To identify speci c imaging phenotypes for hypertensive TAK patients, 14 arteries including bilateral carotid arteries, brachiocephalic trunk, bilateral subclavian arteries, aortic arch, ascending aorta, thoracic aorta, pulmonary artery, abdominal aorta, bilateral renal artery, superior mesenteric artery and celiac axis were included in the cluster analysis by a two-step progress as described previously [26]. Individual arteries were clustered on the presence or absence of arteriographic lesions, and agglomerative, hierarchical clustering was performed. The cluster algorithm started with each individual artery as a single cluster. In successive iterations, the two nearest clusters were merged together on the basis of a measure of similarity to form a new, unique cluster. The process was repeated until all of the data were contained in one cluster. Tree dendograms were created to visualize cluster patterns.
Cox proportional hazards regression model was used to evaluate associations of imaging phenotypes and clinical characteristics with EFS during the follow-up by adjusting for age, sex, disease duration, disease activity, and received medications. Hazard ratios (HR) and 95% con dence intervals (CIs) were reported. The Kaplan-Meier method was used to plot the proportion distribution of EFS in the above subgroups over time with log-rank test. Statistical analyses were performed using SPSS 22.0 (IBM Corp., Armonk, New York, USA). Two-sided p < 0.05 was considered to indicate statistical signi cance. In comparison with non-hypertensive patients, higher prevalence of renal insu ciency (8.8% vs. 2.2%, p = 0.001) and heart failure (11.8% vs. 5.8%, p = 0.009) was observed in hypertensive patients. Imaging types and arterial involvement signi cantly differed (p < 0.001), showing higher prevalence of renal artery involvement (56.9% vs. 13.3%, p < 0.001) and abdominal aorta involvement (51.5% vs. 22.7%, p < 0.001) in patients with hypertension (Supplementary Table S1).

Characteristics of patients with different hypertensive severity
Mild, moderate, and severe hypertension was observed in 48 (23.5%), 62 (30.4%), and 94 (46.1%) cases, respectively. Clinical characteristics of the three categories were summarized in Table 1. Age, sex, and disease duration were similar among the three categories. The prevalence of renal insu ciency (p = 0.048), renal artery involvement (p = 0.043), as well as blood pressure control status (p < 0.001) signi cantly differed among the three hypertension categories. Patients with severe hypertension were more likely to experience failed control of blood pressure than those with mild (12.6% vs. 4.6%, p < 0.001) and moderate hypertension (12.6% vs. 5.3%, p = 0.008), respectively.  Table S2).

Characteristics of patients with different imaging phenotypes
As signi cant differences of artery involvement were demonstrated in hypertensive patients, cluster analysis was further performed to explore new imaging phenotypes for hypertensive TAK population ( Fig. 2): Cluster 1: involvement of abdominal aorta and/or renal artery (n = 56, 27.5%); Cluster 2: involvement of ascending aorta, thoracic aorta, and/or the aortic arch and its branches (n = 38, 18.6%); and Cluster 3: combined involvement of Cluster 1 and Cluster 2 (n = 110, 53.9%). The clinical characteristics of patients with different imaging phenotypes were shown in Table 2. Besides sex (p = 0.007) and age (p < 0.001), the prevalence of baseline features, including renal insu ciency (p = 0.046), heart failure (p = 0.013), cerebral infarction (p = 0.007), severe hypertension (p = 0.014), and severe AR (p = 0.047) differed signi cantly among the three imaging phenotype clusters. The blood pressure control status also differed among the three clusters of imaging phenotypes. The Cluster 1 group had lower prevalence of hypertension control (36.2% vs. 74.3%, p < 0.001) and higher prevalence of failed hypertension control (10.6% vs. 5.7%, p = 0.019) than Cluster 2 group (Fig. 3). In addition, immunosuppressive therapy and the medium kind of antihypertensive drugs, as well as the medication choice did not signi cantly differ among patients with different imaging phenotypes (Supplementary   Table S3).
Kaplan-Meier curves showed that patients with Cluster 1 imaging phenotype might suffer from worse EFS in comparison with Cluster 2 and Cluster 3 imaging phenotype, though this difference was not statistically signi cant (Fig. 4A). Patients with controlled blood pressure showed better EFS during the follow-up (Fig. 4B).

Discussion
The present study aimed to summarize the disease characteristics of hypertensive TAK patients and highlight potential determinants to the EFS. We found that: i) about 33% TAK patients in our cohort suffered from hypertension, among whom, almost half were severe hypertension; ii) three speci c imaging phenotypes were identi ed for hypertensive TAK patients, which could be distinguished from non-hypertensive cases; iii) only 50.8% patients got controlled blood pressure in the present study and the overall EFS was 67.9% by the end of a median 48 months follow-up; iv) patients with controlled hypertension showed better EFS, while imaging phenotype also showed effects on the EFS, though not statistically signi cant.
Previous studies have reported that hypertension occurred in 33-83% TAK patients, with younger disease onset age (mostly < 40 years) [7][8][9][10]21]. One former study even indicated that a combination of hypertension and elevated erythrocyte sedimentation rate (ESR) was useful for diagnosing TAK in patients < 18 years of age [27]. Our data pointed out that 33% TAK patients suffered from hypertension, which was consistent with these previous studies. Furthermore, severe hypertension was observed in almost half of the hypertensive cases in our cohort, and severe hypertensive patients were more likely to complain of renal insu ciency and failure to control the elevated blood pressure. These ndings call for physicians' awareness of the diagnosis of TAK in young individuals presenting with hypertension, especially in those with indecipherable severe hypertension.
Previous studies have revealed that renal artery stenosis-associated hypertension was observed in about 50% of TAK cases [12,27,28]. In the current study, we also found that the renal artery (60%) was the most commonly involved artery in hypertensive TAK patients, and the prevalence of severe and refractory hypertension was signi cantly higher in patients with renal artery stenosis (data not shown), which might support the important role of renal artery stenosis in the causes of hypertension in TAK. In addition, signi cant differences of artery involvement was demonstrated between patients with and without hypertension, wherein it was speculated that hypertensive patients might have speci c imaging phenotypes. We con rmed this by identifying three speci c imaging phenotype clusters in hypertensive patients, which could be distinguished from non-hypertensive cases (Fig. 5). Younger age and worse disease status, especially the prevalence of severe hypertension and renal insu ciency, was observed in patients with Cluster 1 imaging phenotype. What is more, the imaging phenotypes de ned in our study also showed signi cant effects on the EFS. The EFS was signi cantly lower in Cluster 1 (59.6%) than that in Cluster 2, but similar to that in Cluster 3, which may be related to the higher prevalence of renal insu ciency and persistent refractory and/or malignant hypertension, as well as the lower prevalence of blood pressure control in Cluster 1 and Cluster 3. In addition, although renal and abdominal aorta involvement were indicated both in Cluster 1 and Cluster 3, future studies would be needed to determine whether poor prognosis is mainly attributed to this involvement.
Except for renal artery, hypertension in TAK could be caused by multifactorial conditions. In Cluster 2, hypertension might be caused by the involvement of the ascending aorta, thoracic aorta, aortic arch, and its branches instead of the renal and abdominal aorta. Hamida et al. reported that lesions of supraaortic trunks, carotid lesions, and immunosuppressive drugs might contribute to the genesis of hypertension in TAK [29]. Former studies have also found that dysfunctional baroreceptors are possible mechanisms involved in causing hypertension [30]. It is well recognized that a proatherogenic effect occurs in patients with TAK, which may increase arterial stiffness and decrease elasticity of arterial walls that may contribute to elevated blood pressure. In addition, severe AR was observed in 9.3% hypertensive patients in our study, which was a little lower than that reported in a previous study [21]. Aortic regurgitation may be also associated with hypertension in TAK, and is likely caused by directed valvular lesions, aneurysms arising from the aortic annulus, or annular dilation resulting from extensive dilatational changes of the ascending aorta. Furthermore, we also found that co-existence of severe AR was negatively related to the EFS. Thus, echocardiography monitoring is very necessary for TAK population.
In the current investigation, only 50.8% cases had blood pressure controlled during the follow-up, which was relatively low. More importantly, patients with blood pressure control showed signi cantly better EFS. Thus, the main treatment goal for hypertensive TAK patients should be not only to achieve and maintain disease remission, but also to achieve blood pressure control. Combined with the above data, we also made a decision tree diagram using three variables: imaging phenotype, blood pressure control status and co-existence of sever AR (shown as Supplementary Fig S2). Through the diagram, 69.2% patients could be classi ed into the right prognosis group. However, the power and accuracy of the decision tree diagram should be validated in the future, due to the small sample size of the present research.
Our study has two major limitations. First, due to the low incidence of TAK, association analyses between severity and controlled status as well as imaging phenotypic categories of hypertension with the prognosis may be underpowered, which warrants future larger studies to validate our results. Second, the follow-up duration was relatively short, and further studies with larger sample size and longer follow-up duration are needed to validate the results.

Conclusions
In conclusion, 33% TAK patients suffered from hypertension in out cohort, with almost half severe cases. Three speci c imaging phenotypes were identi ed for hypertensive TAK patients. The blood pressure control rate was 50.8%, with overall EFS of 67.9% by the end of the follow-up. Our data support blood pressure control status and speci c imaging phenotypes showed signi cant effects on EFS for hypertensive TAK patients.
Abbreviations Figure 1 Study ow chart. In all, 204 hypertensive Takayasu arteritis patients were enrolled in to the present study from the East China Takayasu arteritis cohort between January 2013 and December 2019. Clinical characteristics and imaging features of each case were evaluated. The main outcome of the investigation was the events free survival by the end of August 30, 2020. Subgroup analysis, according to hypertensive severity and imaging phenotype, was also performed. Cluster 1: involvement of abdominal aorta and/or renal artery; Cluster 2: involvement of ascending aorta, thoracic aorta, and/or the aortic arch and its branches; and Cluster 3: combined involvement of Cluster 1 and Cluster 2.

Figure 2
Tree dendogram for involved arteries of hypertensive and non-hypertensive Takayasu arteritis. Fourteen arteries including bilateral carotid arteries, brachiocephalic trunk, bilateral subclavian arteries, aortic arch, ascending aorta, thoracic aorta, pulmonary artery, abdominal aorta, bilateral renal artery, superior mesenteric artery and celiac axis were included in the cluster analysis by a two-step progress to identify imaging phenotypes for hypertensive population. Three speci c imaging phenotype clusters was identi ed for hypertensive patients (A), which could be distinguished from non-hypertensive cases (B).

Figure 3
Clinical characteristics and outcomes of patients with different imaging phenotypes. Clinical characteristics in the radar map (left) included age, sex, clinical manifestations, and baseline complications. Blood pressure control status as well as outcomes, including prevalence of total events, persistent refractory/malignant hypertension, renal insu ciency, congestive heart failure and cerebrovascular events were shown in the right radar map. AR: aortic regurgitation; Bp: blood pressure. Events free survival in patients with different imaging phenotypes and with different blood control status.
A: Events free survival in patients with different imaging phenotypes. B: Events free survival in patients with different blood pressure control status. Cluster 1: involvement of abdominal aorta and/or renal artery; Cluster 2: involvement of ascending aorta, thoracic aorta, and/or the aortic arch and its branches; and Cluster 3: combined involvement of Cluster 1 and Cluster 2. Decision tree for predicting the prognosis of hypertensive Takayasu arteritis. Using three variables including imaging phenotype, blood pressure control status and co-existence of sever AR, a decision tree diagram was established to predict the disease prognosis. Through the diagram, 69.2% patients could be classi ed into the right prognosis group.

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