Superficial and multiple calcifications and ulceration associate with intraplaque hemorrhage in the carotid atherosclerotic plaque

Superficial and multiple calcifications and ulceration associate with intraplaque hemorrhage in... Objective Intraplaque hemorrhage (IPH) and ulceration of carotid atherosclerotic plaques have been associated with vulnerability while calcification has been conventionally thought protective. However, studies suggested calcification size and location may increase plaque vulnerability. This study explored the association between calcium configurations and ulceration with IPH. Methods One hundred thirty-seven consecutive symptomatic patients scheduled for carotid endarterectomy were recruited. CTA and CTP were performed prior to surgery. Plaque samples were collected for histology. According to the location, calcifications were categorized into superficial, deep and mixed types; according to the size and number, calcifications were classified as thick and thin, multiple and single. Results Seventy-one plaques had IPH (51.8%) and 83 had ulceration (60.6%). The appearance of IPH and ulceration was correlated (r =0.49; p < 0.001). The incidence of multiple, superficial and thin calcifications was significantly higher in lesions with IPH and ulceration compared with those without. After adjusting factors including age, stenosis and ulceration, the presence of calcification [OR (95% CI), 3.0 (1.1-8.2), p = 0.035], multiple calcification [3.9 (1.4-10.9), p = 0.009] and superficial calcification [3.4 (1.1-10.8), p = 0.001] were all associated with IPH. ROC analysis showed that the AUC of superficial and multiple calcifications in detecting IPH was 0.63 and 0.66, respectively (p < 0.05). When the ulceration was combined, AUC increased significantly to 0.82 and 0.83, respectively. Results also showed that patients with lesions of both ulceration and IPH have significantly reduced brain perfusion in the area ipsilateral to the infarction. Conclusions Superficial and multiple calcifications and ulceration were associated with carotid IPH, and they may be a surrogate for higher risk lesions. Key Points � CTA-defined superficial and multiple calcifications in carotid atherosclerotic plaques are independently associated with the presence of intraplaque hemorrhage. � The combination of superficial and multiple calcifications and ulceration is highly predictive of carotid intraplaque hemorrhage. � Patients with lesions of both ulceration and intraplaque hemorrhage have significantly reduced brain perfusion in the area ipsilateral to the infarction. . . . Keywords Stroke Artery Atherosclerosis Calcium Abbreviations * Zhongzhao Teng CBF Cerebral blood flow zt215@cam.ac.uk CBV Cerebral blood volume * Pinjing Hui CEA Carotid endarterectomy pinjing-hui@163.com CT Computed tomography CTA CT angiology Department of Stroke Center, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China CTP CT perfusion hrMRI High-resolution magnetic resonance imaging Department of Medicine, University of Cambridge, Cambridge, UK hs-CRP High-sensitivity C-reactive protein Department of Radiology, University of Cambridge, Level 5, Box IPH Intraplaque hemorrhage 218, Addenbrooke’s Hospital, Hills Rd., Cambridge CB2 0QQ, UK Eur Radiol IQR Interquartile range stability are therefore required to better understand carotid MTT Mean transit time atherosclerotic risk. This study is designed as a comprehen- NASCET North American Symptomatic Carotid sive evaluation of the relationship between different features Endarterectomy Trial of calcification and ulceration with IPH. OR Odds ratio RI Remodeling index TIA Transient ischemic attack TTP Time to peak Materials and Methods UTE Ultrashort echo time Study population Introduction This study was approved by the local ethics committee and all enrolled subjects signed written informed consent. The inclu- Stroke has become the leading cause of death and adult dis- sion criteria [22] were symptomatic patients with luminal ste- abilityinChina [1, 2]. An atherosclerotic lesion located in the nosis ≥ 70% defined by ultrasonography [North American carotid circulation is responsible for 20~30% of ischemic Symptomatic Carotid Endarterectomy Trial (NASCET) crite- stroke, mostly due to plaque rupture [3, 4]. It has been dem- rion] [23] and luminal stenosis < 70% but with recurrent in- onstrated that intraplaque hemorrhage (IPH) is associated with farcts in the ipsilateral hemisphere despite optimal medical plaque progression and instability [5, 6]. The involvement of therapy. Symptomatic lesions were defined as ipsilateral is- hemoglobin-rich plaque hemorrhage in the transformation chemic events, including cerebral infarction, transient ische- from stable to unstable lesions was proposed over 80 years micattack(TIA) andamaurosis fugaxwithin6months. ago [7], the rupture of fragile neovessels being thought to Exclusion criteria were patients with conditions that might initiate and promote IPH development [8]. IPH induces increase high-sensitivity C-reactive protein (hs-CRP) levels intraplaque inflammation by recruiting inflammatory contents [24], including severe peripheral arterial disease and apparent [9], e.g., macrophages, while chronic inflammation links to infection, and those with acute coronary syndromes who had calcium deposits [10]. As a result, IPH has been considered undergone surgery within 90 days. A total of 137 consecutive a biomarker for plaque instability [9]. Plaque ulceration is patients scheduled for carotid endarterectomy (CEA) in the another high-risk feature; though much more common in First Affiliated Hospital of Soochow University were recruit- symptomatic than asymptomatic individuals, it commonly ed from February 2013 to August 2017. Patient demographics leads to fibrous cap rupture and therefore carries an increased are listed in Table 1. risk of ischemic cerebrovascular events [11, 12]. Combined, the presence of both IPH and ulceration carries the highest risk Table 1 Patient demography for recurrent ischemic events [13, 14]. Studies in the past ~20 years showed that high-resolution magnetic resonance imag- Subject characteristic Patients (n =137) ing (hrMRI) can accurately identify these two features [6, 15]. Age (mean) (SD) (year) 68.8 (7.3) Conversely, calcification has traditionally been thought Male (n) (%) 121 (88.3) protective. A systemic review of 24 studies found that asymp- Hypertension (n) (%) 104 (75.9) tomatic patients have more calcium deposits in carotid plaques Hyperlipidemia (n) (%) 92 (67.2) than symptomatic ones [16], supporting earlier observations Diabetes (n)(%) 48 (35.0) [17, 18] that calcification was a sign of plaque stability. BMI (≥ 25) (n)(%) 63 (46.0) However, more recently studies have highlighted a controver- Current or prior smoker (n)(%) 51 (37.2) sial role of calcification with certain sizes [19, 20] and loca- Cerebral infarction or TIA (n)(%) 81 (59.1) tions [21] being associated with increased plaque Coronary artery disease (n) (%) 28 (20.4) vulnerability. hs-CRP (median) [interquartile range] (mg/l) 2.5 [1.1-7.2] Compared with hrMRI, computed tomography angiology Scr (median) [IQR] (μmol/l) 72.0 [63.0-85.5] (CTA) has less capacity to differentiate soft plaque compo- Statin use (n) (%) 74 (54.0) nents, e.g., IPH, while being particularly good at detecting calcium. Moreover, CTA is a more widely available modality Antiplatelet use (n)(%) 73 (53.3) than hrMRI. It would therefore be clinically advantageous to Hyperlipidemia was defined as serum low-density lipoprotein (LDL) extend the use of CTA beyond its current remit, assessing cholesterol > 3.36 mmol/l or total cholesterol (TC) > 5.72 mmol/l or luminal stenosis, and, by assessment of the calcium burden, triglycerides (TG) > 2.3mmol/l predict a plaque’s vulnerability. Detailed analysis of the rela- BMI, body mass index; TIA, transient ischemic attack; hs-CRP, high- tionship between calcium and factors associated with plaque sensitivity C-reactive protein; Scr, serum creatinine Eur Radiol CTA and CTP imaging calcification. Superficial calcification was defined as a calcified nodule located at the intimal-lumen interface or close to the Computerized tomography (CT) scanning was performed lumen [30]. Deep calcification was defined as a calcified nodule using a second-generation, dual-source 64-slice CT scanner located at the media/adventitia border or close to the adventitia. (Somatom Definition Flash, Siemens Healthcare, Forchheim, The presence of both deep and superficial calcification was Germany). The cross-sectional helical scan was performed regarded as a mixed category. According to the maximum followed by the CT perfusion (CTP) scan with a 10-cm range thickness, calcification was classified as either thick (≥ 2mm) covering the basal ganglia and adjacent layers. The tube voltage or thin (< 2 mm). A distinction was also made between single was 80 kV with a current of 150 mAs. Contrast agent (iohexol, and multiple nodules (Fig. 3). All parameters and characteristics 350mg I/ml) 40 ml and saline 60 ml were injected via a cubital were independently evaluated by two experienced radiologists, vein at a rate of 6.0 ml/s using a high-pressure syringe both of whom were blinded to patient clinical presentation and (Germany Ulrich Automatic contrast agent syringe). The scan histopathology findings. started in 8 s after the injection, and the scanning duration was 37 s. About 400 frames were acquired from each patient. Histopathologic evaluation of plaque samples The dual-source CTA scan of the head and neck from the aortic arch to the top of the skull with a slice thickness of 0.5 Plaque samples were cut into proximal and distal parts at the mm was performed 5 min after the CTP scan. A total of 60 ml most stenotic site and immediately fixed in 4% buffered for- contrast agent (iohexol, 350 mg I/ml) and the subsequent 40 malin for 48 h, then decalcified and embedded in paraffin. ml saline solution were injected at a flow rate of 5 ml/s into the Further transverse sections of 4 μm thickness at a 1-mm in- same cubital vein with the high-pressure syringe system. The terval were obtained. Hematoxylin and eosin staining was bolus-tracking technique was used for image acquisition with used to identify IPH according to previously published criteria a region of interest in the common carotid artery and a trigger [31, 32]. Sections were then assessed by two independent at 100 HU. Data acquisition was initiated after the threshold histopathologists blinded to the clinical and imaging findings. was reached in the common carotid artery. The carotid CTA The presence or absence of IPH was recorded. scanning parameters were: rotation speed of 0.33 s/rev, align- ment of 64 × 0.6 mm , voltages of 140 kVand 80 kV, respec- Statistical analysis tively, current of 56 mAs and 234 mAs, pitch of 0.65, field of view of 230 mm and reconstruction thickness of 1 mm. All Statistical analysis was performed with SPSS 19.0 (IBM Corp., CTA images were sent to a post-processing workstation Armonk, NY, USA). Continuous quantitative variables were (Syngo.via) and reconstructed with a thickness of 1 mm. described as mean ± SD or median [interquartile range, IQR] depending on the distribution, while categorical variables were CTA and CTP imaging review described as percentages. The Student’s t, Mann-Whitney U, χ2andFisher’s exact tests were used to compare baseline char- All images were reviewed and analyzed using the Neuro acteristics, CTP parameters and CTA makers between patients VPCT package (Siemens Healthcare, Forchheim, Germany). with and without IPH/ulceration where appropriate. Cerebral blood flow (CBF), cerebral blood volume (CBV), Multivariate regression analysis was used to explore associa- mean transit time (MTT) and time to peak (TTP) were extract- tions between characteristic calcifications and IPH and ulcera- ed for analysis. Multiplanar reformation, curved planar refor- tion. To assess the discriminatory potential of each marker or mation, maximum intensity projection and volume rendering combination of markers in identifying IPH, the area under the were used for the characterization of carotid plaque. curve (AUC) of the receiver-operating characteristic (ROC) The degree of luminal stenosis, plaque thickness, surface were reported with 95% confidence intervals (CI). The interob- ulceration and remodeling index (RI = the maximum wall server agreement was calculated using an intraclass correlation thickness at the most stenotic site/the wall thickness at the near- coefficient or Cohen’s κ statistics based on 20 randomly chosen by disease-free site) were calculated or identified. Positive soft patients assessed by observer A and observer B. A p value < plaque was defined as maximum soft plaque thickness >2 mm 0.05 was assumed to be statistically significant. [25], and a positive remodeling index was reported as RI ≥ 1.1 [26]. The mean plaque Hounsfield unit (HU) was defined as the average HU in the region between the lumen and outer wall Results contour across the whole plaque volume [27]. Ulceration was defined as irregular concavities with a minimum depth of 1 mm Patient characteristics on any plane [28, 29](Fig. 1). The presence of calcification and the location and number of calcific nodules were recorded and One hundred thirty-seven patients were recruited with a mean categorized as either surface (Fig. 2), deep or mixed age of 68.8 ± 7.3 years; 121 (88.3%) were male; 104 (75.9%) Eur Radiol Fig. 1 Plaque ulceration and (A) (B) remodeling. A Presence of ulceration (arrow) was identified. B Remodeling index (RI) was computed as a/b had hypertension, 48 (35.0%) diabetes and 92 (78.8%) hyper- in Fig. 4. Median CBF between groups with and without IPH lipidemia. The majority were receiving medications prior to was significantly different (54.7 [48.2-60.6] versus 56.5 [51.7- the study (54.0% on statin, 53.3% on antiplatelet). More pa- 66.4], p = 0.028). However, no significant difference was tient demographics are shown in Table 1. found in CBV, TTP and MTT. Median TTP and MTT for the group with ulceration were seen to be longer than in the Clinical risk factors, IPH, ulceration and brain group without (11.2 [9.8-12.8] versus 10.1 [9.4-12.4], p = perfusion 0.041; 4.0 [3.7-4.7] vs. 3.8 [3.5-4.4], p = 0.045). On the con- trary, CBF and CBV showed no significant difference be- IPH was found in 71 (51.8%) patients and ulceration in 83 tween the groups with and without ulceration (Table 3). (60.6%). Sixty-two plaques (45.2%) had both IPH and ulcer- ation, and 45 (32.8%) had neither of these features. The ap- The association of CTA-identified plaque features, pearance of IPH and ulceration was significantly correlated (r ulceration and IPH =0.49; p <0.001). As opposed to patients without carotid IPH and ulceration, As shown in Table 4, lesions with IPH showed a higher prev- those with tended to be both older (70.9 ± 6.7 versus 66.5 ± alence of plaque ulceration than those without (87.3% versus 7.3 years, p < 0.001; 70.3 ± 7.2 versus 66.5 ± 6.8 years, p = 31.8%, p < 0.001). The prevalence of calcification, multiple 0.003, respectively) and have a significantly higher level of calcifications, superficial calcification, mixed calcifications serum hs-CRP (3.6 mg/l versus 1.7 mg/l, p = 0.001; 4.9 mg/l and thin calcification was significantly higher in plaques with versus 1.2 mg/l, p < 0.001). Moreover, hypertension was more IPH compared with those without (83.1% versus 60.6%, p = likely to be present in patients with carotid plaque surface 0.003; 52.1% versus 19.7%, p < 0.001; 36.6% versus 10.6%, ulceration than those without (88.0% versus 57.4%, p < p < 0.001; 22.5% versus 9.1%, p = 0.044; 45.1% versus 0.001). Other clinical risk factors did not differ significantly 24.2%, p = 0.011; respectively). However, deep calcification between these two groups as shown in Table 2. was less prevalent in plaques with IPH compared with those CTP parameters between groups with and without IPH without (23.9% versus 40.9%, p = 0.034). Moreover, mean were compared, as listed in Table 3 with an example shown plaque density, maximum total plaque thickness, the incidence Eur Radiol Fig. 2 CTA and pathological (B) (A) image showing superficial calcification and IPH on the internal carotid artery. A and B MPR images of the plaque with a calcified nodule located at the intimal-lumen interface (arrow; B is an axial view of A at the level with calcification). C Eyeball assessment of the CEA specimen with IPH. D Hematoxylin and eosin (×16) stain showing IPH (arrow) (C) (D) Fig. 3 CTA and pathological (A) (B) image showing multiple calcifications and IPH on the internal carotid artery. A and B MPR images of the plaque with multiple calcified nodules within the plaque (arrows; B is an axial view of A at the level with calcifications). C Eyeball assessment of the CEA specimen showing IPH (arrow). D Hematoxylin and eosin (×16) stain showing IPH (arrow) (C) (D) Eur Radiol Table 2 Clinical characteristics between groups with and without IPH and ulceration Clinical characteristics Ulceration (+) Ulceration (-) p value IPH (+) IPH (-) p value (n =83) (n =54) (n =71) (n =71) Age (mean) (SD) (year) 70.3 (7.2) 66.5 (6.8) 0.003 70.9 (6.7) 66.5 (7.3) < 0.001 Male (n) (%) 76 (91.6) 45 (83.3) 0.143 62 (87.3) 59 (89.4) 0.706 Hypertension (n) (%) 73 (88.0) 31 (57.3) < 0.001 57 (80.3) 47 (71.2) 0.215 Hyperlipidemia (n) (%) 55 (66.3) 37 (68.5) 0.784 50 (70.4) 42 (63.6) 0.398 Diabetes (n) (%) 33 (39.8) 15 (27.8) 0.151 26 (36.6) 22 (33.3) 0.687 BMI (≥ 25) (n) (%) 43 (51.8) 20 (37.0) 0.090 37 (52.1) 26 (39.4) 0.136 Current or prior smoker (n) (%) 35 (42.2) 16 (29.6) 0.138 29 (40.8) 22 (33.3) 0.363 Cerebral infarction or TIA (n) (%) 53 (63.9) 28 (51.9) 0.163 45 (63.4) 36 (54.4) 0.293 Coronary artery disease (n) (%) 18 (21.7) 10 (18.5) 0.653 15 (21.1) 13 (19.7) 0.836 hs-CRP (median) [IQR] (mg/l) 4.9 [1.8-11.4] 1.2 [0.6-2.2] < 0.001 3.6 [1.6-11.1] 1.7 [0.8-5.0] 0.001 Scr (median) [IQR] (μcr /l) 73.0 [62.0-85.0] 72.0 [65.0-88.0] 0.925 72.0 [63.0-85.0] 74.0 [63.0-88.0] 0.649 Statin use (n) (%) 41 (49.4) 33 (61.1) 0.179 36 (50.7) 38 (57.6) 0.420 Antiplatelet (n) (%) 47 (56.6) 26 (48.1) 0.331 43 (60.6) 30 (45.5) 0.077 BMI, body mass index; TIA, transient ischemic attack; hs-CRP, high-sensitivity C-reactive protein; Scr, serum creatinine IPH/ulceration (+) or IPH/ulceration (-), carotid plaques with or without intraplaque hemorrhage/ulceration of positive soft plaque, degree of stenosis and thick calcifica- superficial calcification was 0.63 (0.54-0.72) (95% confidence tion showed no significant difference between the two groups. interval), while for multiple calcifications was 0.66 (0.57- Compared with plaques without ulceration, those with ul- 0.75) and for ulceration 0.78 (0.70-0.86). When ulceration ceration showed less severe luminal stenosis (NASCET-de- was combined with either superficial calcification or multiple fined stenosis, 77.3% versus 81.9%, p = 0.018), and the inci- calcifications, the AUC increased significantly [0.82 (0.74- dence of calcification, multiple calcifications, superficial cal- 0.88); 0.83 (0.76-0.89), respectively; both p <0.001]. cification and thin calcification was significantly higher, while deep calcification was significantly less likely in carotid plaques with ulceration (all p <0.05; Table 4). Interobserver agreement In the univariate regression analysis (Table 5), the presence of calcification, multiple calcifications, superficial calcifica- Data from 20 randomly selected patients was used to assess tion, deep calcification, mixed calcifications and thin calcifi- the interobserver agreement. The interobserver intraclass cor- cation was all significantly associated with IPH, but not single relation coefficient for mean plaque HU was 0.92 (0.80-0.97) and thick calcifications. After adjusting for age, NASCET- and 0.89 (0.75-0.96) for plaque maximum thickness. The defined stenosis, mean plaque HU, plaque maximum thick- Cohen κ between two reviewers for presence of ulceration ness, positive remodeling, positive soft plaque and ulceration, was 0.90 (0.80-0.99), 0.89 (0.78-0.99) for positive soft plaque the associations remained for the presence of calcification, and 0.76 (0.60-0.92) for calcification. The interobserver multiple calcification and superficial calcifications (Table 5). agreement of CTP was excellent for CBF [κ: 0.85 (0.66- Receiver-operating characteristic (ROC) analysis showed 0.94)], TTP [κ: 0.95 (0.89-0.98)] and MTT [κ: 0.91 (0.79- the different features’ capacity to identify IPH. The AUC for 0.96)], but moderate for CBV [κ: 0.61 (0.23-0.83)]. Table 3 CTP parameters between groups with and without IPH and ulceration (median [IQR]) CTP parameters Ulceration (+) Ulceration (-) p value IPH (+) IPH (-) p value (n =83) (n =54) (n =71) (n =66) CBF (ml/100 ml/min) 55.2 [48.9-61.6] 57.0 [51.1-65.6] 0.166 54.7 [48.2-60.6] 56.5 [51.7-66.4] 0.028 CBV (ml/100 ml) 3.3 [2.9-3.5] 3.4 [3.0-3.7] 0.186 3.3 [2.9-3.5] 3.4 [3.0-3.7] 0.089 TTP (s) 11.2 [985-12.8] 10.1 [9.4-12.4] 0.041 10.5 [9.5-12.8] 10.8 [9.6-12.6] 0.826 MTT (s) 4.0 [3.7-4.7] 3.8 [3.5-4.4] 0.045 4.0 [3.6-4.7] 3.8 [3.5-4.3] 0.188 CBF, cerebral blood flow; CBV, cerebral blood volume; TTP, time to peak; MTT, mean transit time; Ulceration/IPH (+), carotid plaques with ulceration or intraplaque hemorrhage; Ulceration/IPH (-), carotid plaques without ulceration or intraplaque hemorrhage Eur Radiol (A) (B) (C) (D) (E) (F) (G) Fig. 4 CTA, CTP and the pathological image showing brain perfusion significantly decreased; TTP and MTT prolonged on the right temporal and ipsilateral IPH. A Avolume-rendering image shows severe stenosis at lobe, suggesting right temporal lobe ischemia. G Hematoxylin and eosin the beginning of the right internal carotid artery (arrow). B-F CBF, CBV stain (×16) showing IPH and ruptured fibrous cap Discussion IPH, and many T1-weighted clinical sequences including 3D-TOF and MPRAG can detect the finding [36, 37], while Carotid plaque IPH has been considered an emerging bio- CTA is less useful for differentiating soft contents, such as marker to predict future ischemic cerebrovascular events IPH, lipid and fibrous tissues. However, CTA is more com- [33–35]. hrMRI has an excellent capacity to demonstrate monly available in clinical practice, being significantly faster, Table 4 Carotid plaque CTA markers between groups with and without IPH and ulceration CTA markers Ulceration (+) Ulceration (-) p value IPH (+) IPH (-) p value (n =83) (n =54) (n =71) (n =66) NASCET-defined stenosis (mean) (SD) (%) 77.3 (11.5) 81.9 (10.3) 0.018 77.4 (11.9) 80.6 (10.4) 0.124 Ulceration (n) (%) - - - 62 (87.3) 21 (31.8) < 0.001 Positive remodeling (n) (%) 51 (61.4) 29 (53.7) 0.369 46 (64.8) 34 (51.5) 0.115 Mean plaque density (median) [IQR] (HU) 52 [41-66] 58 [45-66] 0.342 52 [43-65] 57 [44-66] 0.290 Maximum total plaque thickness (mean) (SD) (mm) 4.2 (0.9) 4.1 (1.0) 0.494 4.0 (0.8) 4.3 (1.0) 0.131 Positive soft plaque (n) (%) 57 (68.7) 35 (64.8) 0.638 52 (73.2) 40 (60.6) 0.116 Presence of calcification (n) (%) 64 (77.1) 35 (64.8) 0.116 59 (83.1) 40 (60.6) 0.003 Multiple calcification (n) (%) 39 (47.0) 11 (20.4) 0.002 37 (52.1) 13 (19.7) < 0.001 Single calcification (n) (%) 22 (26.5) 23 (42.6) 0.050 18 (28.2) 27 (44.3) 0.053 Superficial calcification (n) (%) 27 (32.5) 6 (11.1) 0.004 26 (36.6) 7 (10.6) < 0.001 Deep calcification (n) (%) 20 (24.1) 24 (44.4) 0.013 17 (23.9) 27 (40.9) 0.034 Mixed calcification (n) (%) 17 (20.5) 5 (9.3) 0.080 16 (22.5) 6 (9.1) 0.032 Thick calcification (n) (%) 27 (32.5) 24 (44.4) 0.159 27 (38.0) 24 (36.4) 0.840 Thin calcification (n) (%) 37 (44.6) 11(20.4) 0.004 32 (45.1) 16 (24.2) 0.011 Positive soft plaque indicates maximum soft plaque thickness > 2 mm; positive remodeling, remodeling index > 1.1 IPH/ulceration (+) or IPH/ulceration (-), carotid plaques with or without intraplaque hemorrhage/ulceration Eur Radiol Table 5 Relationship between Calcification characteristics Univariate p value Multivariate p value calcification characteristics and OR (95% CI) OR (95% CI) IPH Presence of calcification 3.2 (1.4-7.1) 0.004 3.0 (1.1-8.2) 0.035 Multiple calcifications 4.3 (2.0-9.3) < 0.001 3.9 (1.4-10.9) 0.009 Single calcification 0.5 (0.2-1.0) 0.050 0.6 (0.2-1.4) 0.217 Superficial calcification 4.9 (1.9-12.2) 0.001 3.4 (1.1-10.8) 0.035 Deep calcification 0.5 (0.2-0.9) 0.035 0.6 (0.2-1.7) 0.377 Mixed calcification 2.9 (1.1-8.0) 0.038 2.0 (0.6-7.1) 0.262 Thick calcification 1.1 (0.5-2.1) 0.840 2.3 (0.8-6.2) 0.106 Thin calcification 2.6 (1.2-5.3) 0.012 1.2 (0.5-3.1) 0.710 Multivariate: Adjusted for age, NASCET-defined stenosis, mean plaque HU, plaque maximum thickness, positive remodeling, positive soft plaque and ulceration OR, odds ratio; CI, confidence interval relative to hrMRI, with different and fewer contraindications The underlying mechanism behind the relationship of IPH than MR imaging in general. CTA imaging has favorable and superficial calcification in carotid plaques is unclear. It properties of its own, in particular its ability to define and may be that calcium, being much stiffer than the soft compo- characterize calcification [38, 39] though still a relatively con- nents such as the fibrous cap, introduces a stiffness mismatch troversial marker of plaque instability. Because of its ease and within the structure when present. This mismatch will create a availability, the use of CTA for the purpose of categorizing high stress concentration when calcium is located in the region high-risk plaque is appealing. As shown in this study, calcium closest to the lumen or directly on the lumen surface [21, 45]. burden and ulceration, readily identifiable on CTA, are asso- High mechanical loading then has the potential to damage ciated with higher risk plaque features such as IPH. The results local tissues, particularly the thinner fibrous caps and fragile obtained show CTA defined superficial and multiple calcifi- walls of neovessels, thereby promoting the formation and de- cation in particular to be associated with IPH both before and velopment of IPH and plaque rupture [46]. On the other hand, after adjusting confounding factors. Interestingly, the associa- deep calcification being further away from the lumen has little tion was not seen with thick calcification. The results imply or no impact on plaque stress. Moreover, it could act as a CTA-defined superficial and multiple calcifications may be barrier to the growth of the vasa vasorum from the adventitia useful indirect biomarkers for the identification of higher risk to the intima preventing IPH formation. Our study went on to lesions, those containing IPH, before hrMRI becomes more show the association of multiple calcifications with carotid readily available. Although for the detection of IPH, specific IPH, which may be attributable to a similar mechanism. In carotid surface coils and MR sequences are not mandatory, case of multiple calcium nodules, in particular where two because of the small size of IPH in the lesion, dedicated nodules are close together, connective tissues between them multi-channel carotid surface coil and MR sequences, e.g., a will be subject to high mechanical loading. As a consequence, direct thrombus imaging sequence, MPRAGE (magnetiza- the local disruption and potential for rupture may exist. tion-prepared rapid acquisition gradient-echo) and SNAP (si- In this study, a weak correlation was found between the size multaneous non-contrast angiography and intraplaque hemor- (i.e., the maximum calcification thickness) of calcification and rhage), are recommended. IPH within the carotid plaque. This is different from findings of Although in general calcium is considered a protective fac- previous studies where the volume and length of calcifications tor, increasing evidence suggests size [20, 40] and location were independently associated with IPH and major adverse may influence its effect and in certain configurations increase cardiovascular events [20, 40]. Results obtained from this study vulnerability. In a study of 63 patients by Xu et al. [41], certain showed that age and hs-CRP level were associated with both locations of hrMRI-defined calcium were found to be associ- IPH and ulceration. This was in agreement with previous find- ated with IPH plaque. This was confirmed in a study using ings that IPH was found more often in elderly patients and those time of flight and MPRAGE where IPH was more likely to be with increased hs-CRP levels [24, 47]. found in lesions with superficial compared with deep calcium The strong association of ulceration and IPH demonstrated [42], despite the fact that the extremely short T1 value of MRI in this study agreed with previous findings [27]. Both IPH and makes calcium detection challenging. Although ultrashort ulceration were found in 62 patients (45.3%), only 9 plaques echo time (UTE) [43] and gray blood [44] MR sequences have (6.6%) had IPH but no ulceration, 21 plaques (15.3%) showed been developed for the detection of calcium, the availability of ulceration but no IPH, and neither IPH nor ulceration was found in 45 plaques (32.8%). Superficial calcification and multiple such imaging techniques is limited. Eur Radiol Open Access This article is distributed under the terms of the Creative calcifications were observed more often in plaques with IPH Commons Attribution 4.0 International License (http:// and ulceration than those with neither IPH nor ulceration. creativecommons.org/licenses/by/4.0/), which permits unrestricted use, This study shows how detailed plaque characteristics may distribution, and reproduction in any medium, provided you give appro- associate with brain perfusion (Table 3). It was observed that priate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. patients with lesions containing IPH have lower CBF compared with those without. For patients with ulcerated carotid plaque, therewas alongerTTP andMMT in the ipsilateral infarction References area. Supporting this, the study found that patients with lesions with both IPH and ulceration had poorer brain perfusion in the 1. 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Superficial and multiple calcifications and ulceration associate with intraplaque hemorrhage in the carotid atherosclerotic plaque

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Medicine & Public Health; Imaging / Radiology; Diagnostic Radiology; Interventional Radiology; Neuroradiology; Ultrasound; Internal Medicine
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0938-7994
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10.1007/s00330-018-5535-7
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Abstract

Objective Intraplaque hemorrhage (IPH) and ulceration of carotid atherosclerotic plaques have been associated with vulnerability while calcification has been conventionally thought protective. However, studies suggested calcification size and location may increase plaque vulnerability. This study explored the association between calcium configurations and ulceration with IPH. Methods One hundred thirty-seven consecutive symptomatic patients scheduled for carotid endarterectomy were recruited. CTA and CTP were performed prior to surgery. Plaque samples were collected for histology. According to the location, calcifications were categorized into superficial, deep and mixed types; according to the size and number, calcifications were classified as thick and thin, multiple and single. Results Seventy-one plaques had IPH (51.8%) and 83 had ulceration (60.6%). The appearance of IPH and ulceration was correlated (r =0.49; p < 0.001). The incidence of multiple, superficial and thin calcifications was significantly higher in lesions with IPH and ulceration compared with those without. After adjusting factors including age, stenosis and ulceration, the presence of calcification [OR (95% CI), 3.0 (1.1-8.2), p = 0.035], multiple calcification [3.9 (1.4-10.9), p = 0.009] and superficial calcification [3.4 (1.1-10.8), p = 0.001] were all associated with IPH. ROC analysis showed that the AUC of superficial and multiple calcifications in detecting IPH was 0.63 and 0.66, respectively (p < 0.05). When the ulceration was combined, AUC increased significantly to 0.82 and 0.83, respectively. Results also showed that patients with lesions of both ulceration and IPH have significantly reduced brain perfusion in the area ipsilateral to the infarction. Conclusions Superficial and multiple calcifications and ulceration were associated with carotid IPH, and they may be a surrogate for higher risk lesions. Key Points � CTA-defined superficial and multiple calcifications in carotid atherosclerotic plaques are independently associated with the presence of intraplaque hemorrhage. � The combination of superficial and multiple calcifications and ulceration is highly predictive of carotid intraplaque hemorrhage. � Patients with lesions of both ulceration and intraplaque hemorrhage have significantly reduced brain perfusion in the area ipsilateral to the infarction. . . . Keywords Stroke Artery Atherosclerosis Calcium Abbreviations * Zhongzhao Teng CBF Cerebral blood flow zt215@cam.ac.uk CBV Cerebral blood volume * Pinjing Hui CEA Carotid endarterectomy pinjing-hui@163.com CT Computed tomography CTA CT angiology Department of Stroke Center, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China CTP CT perfusion hrMRI High-resolution magnetic resonance imaging Department of Medicine, University of Cambridge, Cambridge, UK hs-CRP High-sensitivity C-reactive protein Department of Radiology, University of Cambridge, Level 5, Box IPH Intraplaque hemorrhage 218, Addenbrooke’s Hospital, Hills Rd., Cambridge CB2 0QQ, UK Eur Radiol IQR Interquartile range stability are therefore required to better understand carotid MTT Mean transit time atherosclerotic risk. This study is designed as a comprehen- NASCET North American Symptomatic Carotid sive evaluation of the relationship between different features Endarterectomy Trial of calcification and ulceration with IPH. OR Odds ratio RI Remodeling index TIA Transient ischemic attack TTP Time to peak Materials and Methods UTE Ultrashort echo time Study population Introduction This study was approved by the local ethics committee and all enrolled subjects signed written informed consent. The inclu- Stroke has become the leading cause of death and adult dis- sion criteria [22] were symptomatic patients with luminal ste- abilityinChina [1, 2]. An atherosclerotic lesion located in the nosis ≥ 70% defined by ultrasonography [North American carotid circulation is responsible for 20~30% of ischemic Symptomatic Carotid Endarterectomy Trial (NASCET) crite- stroke, mostly due to plaque rupture [3, 4]. It has been dem- rion] [23] and luminal stenosis < 70% but with recurrent in- onstrated that intraplaque hemorrhage (IPH) is associated with farcts in the ipsilateral hemisphere despite optimal medical plaque progression and instability [5, 6]. The involvement of therapy. Symptomatic lesions were defined as ipsilateral is- hemoglobin-rich plaque hemorrhage in the transformation chemic events, including cerebral infarction, transient ische- from stable to unstable lesions was proposed over 80 years micattack(TIA) andamaurosis fugaxwithin6months. ago [7], the rupture of fragile neovessels being thought to Exclusion criteria were patients with conditions that might initiate and promote IPH development [8]. IPH induces increase high-sensitivity C-reactive protein (hs-CRP) levels intraplaque inflammation by recruiting inflammatory contents [24], including severe peripheral arterial disease and apparent [9], e.g., macrophages, while chronic inflammation links to infection, and those with acute coronary syndromes who had calcium deposits [10]. As a result, IPH has been considered undergone surgery within 90 days. A total of 137 consecutive a biomarker for plaque instability [9]. Plaque ulceration is patients scheduled for carotid endarterectomy (CEA) in the another high-risk feature; though much more common in First Affiliated Hospital of Soochow University were recruit- symptomatic than asymptomatic individuals, it commonly ed from February 2013 to August 2017. Patient demographics leads to fibrous cap rupture and therefore carries an increased are listed in Table 1. risk of ischemic cerebrovascular events [11, 12]. Combined, the presence of both IPH and ulceration carries the highest risk Table 1 Patient demography for recurrent ischemic events [13, 14]. Studies in the past ~20 years showed that high-resolution magnetic resonance imag- Subject characteristic Patients (n =137) ing (hrMRI) can accurately identify these two features [6, 15]. Age (mean) (SD) (year) 68.8 (7.3) Conversely, calcification has traditionally been thought Male (n) (%) 121 (88.3) protective. A systemic review of 24 studies found that asymp- Hypertension (n) (%) 104 (75.9) tomatic patients have more calcium deposits in carotid plaques Hyperlipidemia (n) (%) 92 (67.2) than symptomatic ones [16], supporting earlier observations Diabetes (n)(%) 48 (35.0) [17, 18] that calcification was a sign of plaque stability. BMI (≥ 25) (n)(%) 63 (46.0) However, more recently studies have highlighted a controver- Current or prior smoker (n)(%) 51 (37.2) sial role of calcification with certain sizes [19, 20] and loca- Cerebral infarction or TIA (n)(%) 81 (59.1) tions [21] being associated with increased plaque Coronary artery disease (n) (%) 28 (20.4) vulnerability. hs-CRP (median) [interquartile range] (mg/l) 2.5 [1.1-7.2] Compared with hrMRI, computed tomography angiology Scr (median) [IQR] (μmol/l) 72.0 [63.0-85.5] (CTA) has less capacity to differentiate soft plaque compo- Statin use (n) (%) 74 (54.0) nents, e.g., IPH, while being particularly good at detecting calcium. Moreover, CTA is a more widely available modality Antiplatelet use (n)(%) 73 (53.3) than hrMRI. It would therefore be clinically advantageous to Hyperlipidemia was defined as serum low-density lipoprotein (LDL) extend the use of CTA beyond its current remit, assessing cholesterol > 3.36 mmol/l or total cholesterol (TC) > 5.72 mmol/l or luminal stenosis, and, by assessment of the calcium burden, triglycerides (TG) > 2.3mmol/l predict a plaque’s vulnerability. Detailed analysis of the rela- BMI, body mass index; TIA, transient ischemic attack; hs-CRP, high- tionship between calcium and factors associated with plaque sensitivity C-reactive protein; Scr, serum creatinine Eur Radiol CTA and CTP imaging calcification. Superficial calcification was defined as a calcified nodule located at the intimal-lumen interface or close to the Computerized tomography (CT) scanning was performed lumen [30]. Deep calcification was defined as a calcified nodule using a second-generation, dual-source 64-slice CT scanner located at the media/adventitia border or close to the adventitia. (Somatom Definition Flash, Siemens Healthcare, Forchheim, The presence of both deep and superficial calcification was Germany). The cross-sectional helical scan was performed regarded as a mixed category. According to the maximum followed by the CT perfusion (CTP) scan with a 10-cm range thickness, calcification was classified as either thick (≥ 2mm) covering the basal ganglia and adjacent layers. The tube voltage or thin (< 2 mm). A distinction was also made between single was 80 kV with a current of 150 mAs. Contrast agent (iohexol, and multiple nodules (Fig. 3). All parameters and characteristics 350mg I/ml) 40 ml and saline 60 ml were injected via a cubital were independently evaluated by two experienced radiologists, vein at a rate of 6.0 ml/s using a high-pressure syringe both of whom were blinded to patient clinical presentation and (Germany Ulrich Automatic contrast agent syringe). The scan histopathology findings. started in 8 s after the injection, and the scanning duration was 37 s. About 400 frames were acquired from each patient. Histopathologic evaluation of plaque samples The dual-source CTA scan of the head and neck from the aortic arch to the top of the skull with a slice thickness of 0.5 Plaque samples were cut into proximal and distal parts at the mm was performed 5 min after the CTP scan. A total of 60 ml most stenotic site and immediately fixed in 4% buffered for- contrast agent (iohexol, 350 mg I/ml) and the subsequent 40 malin for 48 h, then decalcified and embedded in paraffin. ml saline solution were injected at a flow rate of 5 ml/s into the Further transverse sections of 4 μm thickness at a 1-mm in- same cubital vein with the high-pressure syringe system. The terval were obtained. Hematoxylin and eosin staining was bolus-tracking technique was used for image acquisition with used to identify IPH according to previously published criteria a region of interest in the common carotid artery and a trigger [31, 32]. Sections were then assessed by two independent at 100 HU. Data acquisition was initiated after the threshold histopathologists blinded to the clinical and imaging findings. was reached in the common carotid artery. The carotid CTA The presence or absence of IPH was recorded. scanning parameters were: rotation speed of 0.33 s/rev, align- ment of 64 × 0.6 mm , voltages of 140 kVand 80 kV, respec- Statistical analysis tively, current of 56 mAs and 234 mAs, pitch of 0.65, field of view of 230 mm and reconstruction thickness of 1 mm. All Statistical analysis was performed with SPSS 19.0 (IBM Corp., CTA images were sent to a post-processing workstation Armonk, NY, USA). Continuous quantitative variables were (Syngo.via) and reconstructed with a thickness of 1 mm. described as mean ± SD or median [interquartile range, IQR] depending on the distribution, while categorical variables were CTA and CTP imaging review described as percentages. The Student’s t, Mann-Whitney U, χ2andFisher’s exact tests were used to compare baseline char- All images were reviewed and analyzed using the Neuro acteristics, CTP parameters and CTA makers between patients VPCT package (Siemens Healthcare, Forchheim, Germany). with and without IPH/ulceration where appropriate. Cerebral blood flow (CBF), cerebral blood volume (CBV), Multivariate regression analysis was used to explore associa- mean transit time (MTT) and time to peak (TTP) were extract- tions between characteristic calcifications and IPH and ulcera- ed for analysis. Multiplanar reformation, curved planar refor- tion. To assess the discriminatory potential of each marker or mation, maximum intensity projection and volume rendering combination of markers in identifying IPH, the area under the were used for the characterization of carotid plaque. curve (AUC) of the receiver-operating characteristic (ROC) The degree of luminal stenosis, plaque thickness, surface were reported with 95% confidence intervals (CI). The interob- ulceration and remodeling index (RI = the maximum wall server agreement was calculated using an intraclass correlation thickness at the most stenotic site/the wall thickness at the near- coefficient or Cohen’s κ statistics based on 20 randomly chosen by disease-free site) were calculated or identified. Positive soft patients assessed by observer A and observer B. A p value < plaque was defined as maximum soft plaque thickness >2 mm 0.05 was assumed to be statistically significant. [25], and a positive remodeling index was reported as RI ≥ 1.1 [26]. The mean plaque Hounsfield unit (HU) was defined as the average HU in the region between the lumen and outer wall Results contour across the whole plaque volume [27]. Ulceration was defined as irregular concavities with a minimum depth of 1 mm Patient characteristics on any plane [28, 29](Fig. 1). The presence of calcification and the location and number of calcific nodules were recorded and One hundred thirty-seven patients were recruited with a mean categorized as either surface (Fig. 2), deep or mixed age of 68.8 ± 7.3 years; 121 (88.3%) were male; 104 (75.9%) Eur Radiol Fig. 1 Plaque ulceration and (A) (B) remodeling. A Presence of ulceration (arrow) was identified. B Remodeling index (RI) was computed as a/b had hypertension, 48 (35.0%) diabetes and 92 (78.8%) hyper- in Fig. 4. Median CBF between groups with and without IPH lipidemia. The majority were receiving medications prior to was significantly different (54.7 [48.2-60.6] versus 56.5 [51.7- the study (54.0% on statin, 53.3% on antiplatelet). More pa- 66.4], p = 0.028). However, no significant difference was tient demographics are shown in Table 1. found in CBV, TTP and MTT. Median TTP and MTT for the group with ulceration were seen to be longer than in the Clinical risk factors, IPH, ulceration and brain group without (11.2 [9.8-12.8] versus 10.1 [9.4-12.4], p = perfusion 0.041; 4.0 [3.7-4.7] vs. 3.8 [3.5-4.4], p = 0.045). On the con- trary, CBF and CBV showed no significant difference be- IPH was found in 71 (51.8%) patients and ulceration in 83 tween the groups with and without ulceration (Table 3). (60.6%). Sixty-two plaques (45.2%) had both IPH and ulcer- ation, and 45 (32.8%) had neither of these features. The ap- The association of CTA-identified plaque features, pearance of IPH and ulceration was significantly correlated (r ulceration and IPH =0.49; p <0.001). As opposed to patients without carotid IPH and ulceration, As shown in Table 4, lesions with IPH showed a higher prev- those with tended to be both older (70.9 ± 6.7 versus 66.5 ± alence of plaque ulceration than those without (87.3% versus 7.3 years, p < 0.001; 70.3 ± 7.2 versus 66.5 ± 6.8 years, p = 31.8%, p < 0.001). The prevalence of calcification, multiple 0.003, respectively) and have a significantly higher level of calcifications, superficial calcification, mixed calcifications serum hs-CRP (3.6 mg/l versus 1.7 mg/l, p = 0.001; 4.9 mg/l and thin calcification was significantly higher in plaques with versus 1.2 mg/l, p < 0.001). Moreover, hypertension was more IPH compared with those without (83.1% versus 60.6%, p = likely to be present in patients with carotid plaque surface 0.003; 52.1% versus 19.7%, p < 0.001; 36.6% versus 10.6%, ulceration than those without (88.0% versus 57.4%, p < p < 0.001; 22.5% versus 9.1%, p = 0.044; 45.1% versus 0.001). Other clinical risk factors did not differ significantly 24.2%, p = 0.011; respectively). However, deep calcification between these two groups as shown in Table 2. was less prevalent in plaques with IPH compared with those CTP parameters between groups with and without IPH without (23.9% versus 40.9%, p = 0.034). Moreover, mean were compared, as listed in Table 3 with an example shown plaque density, maximum total plaque thickness, the incidence Eur Radiol Fig. 2 CTA and pathological (B) (A) image showing superficial calcification and IPH on the internal carotid artery. A and B MPR images of the plaque with a calcified nodule located at the intimal-lumen interface (arrow; B is an axial view of A at the level with calcification). C Eyeball assessment of the CEA specimen with IPH. D Hematoxylin and eosin (×16) stain showing IPH (arrow) (C) (D) Fig. 3 CTA and pathological (A) (B) image showing multiple calcifications and IPH on the internal carotid artery. A and B MPR images of the plaque with multiple calcified nodules within the plaque (arrows; B is an axial view of A at the level with calcifications). C Eyeball assessment of the CEA specimen showing IPH (arrow). D Hematoxylin and eosin (×16) stain showing IPH (arrow) (C) (D) Eur Radiol Table 2 Clinical characteristics between groups with and without IPH and ulceration Clinical characteristics Ulceration (+) Ulceration (-) p value IPH (+) IPH (-) p value (n =83) (n =54) (n =71) (n =71) Age (mean) (SD) (year) 70.3 (7.2) 66.5 (6.8) 0.003 70.9 (6.7) 66.5 (7.3) < 0.001 Male (n) (%) 76 (91.6) 45 (83.3) 0.143 62 (87.3) 59 (89.4) 0.706 Hypertension (n) (%) 73 (88.0) 31 (57.3) < 0.001 57 (80.3) 47 (71.2) 0.215 Hyperlipidemia (n) (%) 55 (66.3) 37 (68.5) 0.784 50 (70.4) 42 (63.6) 0.398 Diabetes (n) (%) 33 (39.8) 15 (27.8) 0.151 26 (36.6) 22 (33.3) 0.687 BMI (≥ 25) (n) (%) 43 (51.8) 20 (37.0) 0.090 37 (52.1) 26 (39.4) 0.136 Current or prior smoker (n) (%) 35 (42.2) 16 (29.6) 0.138 29 (40.8) 22 (33.3) 0.363 Cerebral infarction or TIA (n) (%) 53 (63.9) 28 (51.9) 0.163 45 (63.4) 36 (54.4) 0.293 Coronary artery disease (n) (%) 18 (21.7) 10 (18.5) 0.653 15 (21.1) 13 (19.7) 0.836 hs-CRP (median) [IQR] (mg/l) 4.9 [1.8-11.4] 1.2 [0.6-2.2] < 0.001 3.6 [1.6-11.1] 1.7 [0.8-5.0] 0.001 Scr (median) [IQR] (μcr /l) 73.0 [62.0-85.0] 72.0 [65.0-88.0] 0.925 72.0 [63.0-85.0] 74.0 [63.0-88.0] 0.649 Statin use (n) (%) 41 (49.4) 33 (61.1) 0.179 36 (50.7) 38 (57.6) 0.420 Antiplatelet (n) (%) 47 (56.6) 26 (48.1) 0.331 43 (60.6) 30 (45.5) 0.077 BMI, body mass index; TIA, transient ischemic attack; hs-CRP, high-sensitivity C-reactive protein; Scr, serum creatinine IPH/ulceration (+) or IPH/ulceration (-), carotid plaques with or without intraplaque hemorrhage/ulceration of positive soft plaque, degree of stenosis and thick calcifica- superficial calcification was 0.63 (0.54-0.72) (95% confidence tion showed no significant difference between the two groups. interval), while for multiple calcifications was 0.66 (0.57- Compared with plaques without ulceration, those with ul- 0.75) and for ulceration 0.78 (0.70-0.86). When ulceration ceration showed less severe luminal stenosis (NASCET-de- was combined with either superficial calcification or multiple fined stenosis, 77.3% versus 81.9%, p = 0.018), and the inci- calcifications, the AUC increased significantly [0.82 (0.74- dence of calcification, multiple calcifications, superficial cal- 0.88); 0.83 (0.76-0.89), respectively; both p <0.001]. cification and thin calcification was significantly higher, while deep calcification was significantly less likely in carotid plaques with ulceration (all p <0.05; Table 4). Interobserver agreement In the univariate regression analysis (Table 5), the presence of calcification, multiple calcifications, superficial calcifica- Data from 20 randomly selected patients was used to assess tion, deep calcification, mixed calcifications and thin calcifi- the interobserver agreement. The interobserver intraclass cor- cation was all significantly associated with IPH, but not single relation coefficient for mean plaque HU was 0.92 (0.80-0.97) and thick calcifications. After adjusting for age, NASCET- and 0.89 (0.75-0.96) for plaque maximum thickness. The defined stenosis, mean plaque HU, plaque maximum thick- Cohen κ between two reviewers for presence of ulceration ness, positive remodeling, positive soft plaque and ulceration, was 0.90 (0.80-0.99), 0.89 (0.78-0.99) for positive soft plaque the associations remained for the presence of calcification, and 0.76 (0.60-0.92) for calcification. The interobserver multiple calcification and superficial calcifications (Table 5). agreement of CTP was excellent for CBF [κ: 0.85 (0.66- Receiver-operating characteristic (ROC) analysis showed 0.94)], TTP [κ: 0.95 (0.89-0.98)] and MTT [κ: 0.91 (0.79- the different features’ capacity to identify IPH. The AUC for 0.96)], but moderate for CBV [κ: 0.61 (0.23-0.83)]. Table 3 CTP parameters between groups with and without IPH and ulceration (median [IQR]) CTP parameters Ulceration (+) Ulceration (-) p value IPH (+) IPH (-) p value (n =83) (n =54) (n =71) (n =66) CBF (ml/100 ml/min) 55.2 [48.9-61.6] 57.0 [51.1-65.6] 0.166 54.7 [48.2-60.6] 56.5 [51.7-66.4] 0.028 CBV (ml/100 ml) 3.3 [2.9-3.5] 3.4 [3.0-3.7] 0.186 3.3 [2.9-3.5] 3.4 [3.0-3.7] 0.089 TTP (s) 11.2 [985-12.8] 10.1 [9.4-12.4] 0.041 10.5 [9.5-12.8] 10.8 [9.6-12.6] 0.826 MTT (s) 4.0 [3.7-4.7] 3.8 [3.5-4.4] 0.045 4.0 [3.6-4.7] 3.8 [3.5-4.3] 0.188 CBF, cerebral blood flow; CBV, cerebral blood volume; TTP, time to peak; MTT, mean transit time; Ulceration/IPH (+), carotid plaques with ulceration or intraplaque hemorrhage; Ulceration/IPH (-), carotid plaques without ulceration or intraplaque hemorrhage Eur Radiol (A) (B) (C) (D) (E) (F) (G) Fig. 4 CTA, CTP and the pathological image showing brain perfusion significantly decreased; TTP and MTT prolonged on the right temporal and ipsilateral IPH. A Avolume-rendering image shows severe stenosis at lobe, suggesting right temporal lobe ischemia. G Hematoxylin and eosin the beginning of the right internal carotid artery (arrow). B-F CBF, CBV stain (×16) showing IPH and ruptured fibrous cap Discussion IPH, and many T1-weighted clinical sequences including 3D-TOF and MPRAG can detect the finding [36, 37], while Carotid plaque IPH has been considered an emerging bio- CTA is less useful for differentiating soft contents, such as marker to predict future ischemic cerebrovascular events IPH, lipid and fibrous tissues. However, CTA is more com- [33–35]. hrMRI has an excellent capacity to demonstrate monly available in clinical practice, being significantly faster, Table 4 Carotid plaque CTA markers between groups with and without IPH and ulceration CTA markers Ulceration (+) Ulceration (-) p value IPH (+) IPH (-) p value (n =83) (n =54) (n =71) (n =66) NASCET-defined stenosis (mean) (SD) (%) 77.3 (11.5) 81.9 (10.3) 0.018 77.4 (11.9) 80.6 (10.4) 0.124 Ulceration (n) (%) - - - 62 (87.3) 21 (31.8) < 0.001 Positive remodeling (n) (%) 51 (61.4) 29 (53.7) 0.369 46 (64.8) 34 (51.5) 0.115 Mean plaque density (median) [IQR] (HU) 52 [41-66] 58 [45-66] 0.342 52 [43-65] 57 [44-66] 0.290 Maximum total plaque thickness (mean) (SD) (mm) 4.2 (0.9) 4.1 (1.0) 0.494 4.0 (0.8) 4.3 (1.0) 0.131 Positive soft plaque (n) (%) 57 (68.7) 35 (64.8) 0.638 52 (73.2) 40 (60.6) 0.116 Presence of calcification (n) (%) 64 (77.1) 35 (64.8) 0.116 59 (83.1) 40 (60.6) 0.003 Multiple calcification (n) (%) 39 (47.0) 11 (20.4) 0.002 37 (52.1) 13 (19.7) < 0.001 Single calcification (n) (%) 22 (26.5) 23 (42.6) 0.050 18 (28.2) 27 (44.3) 0.053 Superficial calcification (n) (%) 27 (32.5) 6 (11.1) 0.004 26 (36.6) 7 (10.6) < 0.001 Deep calcification (n) (%) 20 (24.1) 24 (44.4) 0.013 17 (23.9) 27 (40.9) 0.034 Mixed calcification (n) (%) 17 (20.5) 5 (9.3) 0.080 16 (22.5) 6 (9.1) 0.032 Thick calcification (n) (%) 27 (32.5) 24 (44.4) 0.159 27 (38.0) 24 (36.4) 0.840 Thin calcification (n) (%) 37 (44.6) 11(20.4) 0.004 32 (45.1) 16 (24.2) 0.011 Positive soft plaque indicates maximum soft plaque thickness > 2 mm; positive remodeling, remodeling index > 1.1 IPH/ulceration (+) or IPH/ulceration (-), carotid plaques with or without intraplaque hemorrhage/ulceration Eur Radiol Table 5 Relationship between Calcification characteristics Univariate p value Multivariate p value calcification characteristics and OR (95% CI) OR (95% CI) IPH Presence of calcification 3.2 (1.4-7.1) 0.004 3.0 (1.1-8.2) 0.035 Multiple calcifications 4.3 (2.0-9.3) < 0.001 3.9 (1.4-10.9) 0.009 Single calcification 0.5 (0.2-1.0) 0.050 0.6 (0.2-1.4) 0.217 Superficial calcification 4.9 (1.9-12.2) 0.001 3.4 (1.1-10.8) 0.035 Deep calcification 0.5 (0.2-0.9) 0.035 0.6 (0.2-1.7) 0.377 Mixed calcification 2.9 (1.1-8.0) 0.038 2.0 (0.6-7.1) 0.262 Thick calcification 1.1 (0.5-2.1) 0.840 2.3 (0.8-6.2) 0.106 Thin calcification 2.6 (1.2-5.3) 0.012 1.2 (0.5-3.1) 0.710 Multivariate: Adjusted for age, NASCET-defined stenosis, mean plaque HU, plaque maximum thickness, positive remodeling, positive soft plaque and ulceration OR, odds ratio; CI, confidence interval relative to hrMRI, with different and fewer contraindications The underlying mechanism behind the relationship of IPH than MR imaging in general. CTA imaging has favorable and superficial calcification in carotid plaques is unclear. It properties of its own, in particular its ability to define and may be that calcium, being much stiffer than the soft compo- characterize calcification [38, 39] though still a relatively con- nents such as the fibrous cap, introduces a stiffness mismatch troversial marker of plaque instability. Because of its ease and within the structure when present. This mismatch will create a availability, the use of CTA for the purpose of categorizing high stress concentration when calcium is located in the region high-risk plaque is appealing. As shown in this study, calcium closest to the lumen or directly on the lumen surface [21, 45]. burden and ulceration, readily identifiable on CTA, are asso- High mechanical loading then has the potential to damage ciated with higher risk plaque features such as IPH. The results local tissues, particularly the thinner fibrous caps and fragile obtained show CTA defined superficial and multiple calcifi- walls of neovessels, thereby promoting the formation and de- cation in particular to be associated with IPH both before and velopment of IPH and plaque rupture [46]. On the other hand, after adjusting confounding factors. Interestingly, the associa- deep calcification being further away from the lumen has little tion was not seen with thick calcification. The results imply or no impact on plaque stress. Moreover, it could act as a CTA-defined superficial and multiple calcifications may be barrier to the growth of the vasa vasorum from the adventitia useful indirect biomarkers for the identification of higher risk to the intima preventing IPH formation. Our study went on to lesions, those containing IPH, before hrMRI becomes more show the association of multiple calcifications with carotid readily available. Although for the detection of IPH, specific IPH, which may be attributable to a similar mechanism. In carotid surface coils and MR sequences are not mandatory, case of multiple calcium nodules, in particular where two because of the small size of IPH in the lesion, dedicated nodules are close together, connective tissues between them multi-channel carotid surface coil and MR sequences, e.g., a will be subject to high mechanical loading. As a consequence, direct thrombus imaging sequence, MPRAGE (magnetiza- the local disruption and potential for rupture may exist. tion-prepared rapid acquisition gradient-echo) and SNAP (si- In this study, a weak correlation was found between the size multaneous non-contrast angiography and intraplaque hemor- (i.e., the maximum calcification thickness) of calcification and rhage), are recommended. IPH within the carotid plaque. This is different from findings of Although in general calcium is considered a protective fac- previous studies where the volume and length of calcifications tor, increasing evidence suggests size [20, 40] and location were independently associated with IPH and major adverse may influence its effect and in certain configurations increase cardiovascular events [20, 40]. Results obtained from this study vulnerability. In a study of 63 patients by Xu et al. [41], certain showed that age and hs-CRP level were associated with both locations of hrMRI-defined calcium were found to be associ- IPH and ulceration. This was in agreement with previous find- ated with IPH plaque. This was confirmed in a study using ings that IPH was found more often in elderly patients and those time of flight and MPRAGE where IPH was more likely to be with increased hs-CRP levels [24, 47]. found in lesions with superficial compared with deep calcium The strong association of ulceration and IPH demonstrated [42], despite the fact that the extremely short T1 value of MRI in this study agreed with previous findings [27]. Both IPH and makes calcium detection challenging. Although ultrashort ulceration were found in 62 patients (45.3%), only 9 plaques echo time (UTE) [43] and gray blood [44] MR sequences have (6.6%) had IPH but no ulceration, 21 plaques (15.3%) showed been developed for the detection of calcium, the availability of ulceration but no IPH, and neither IPH nor ulceration was found in 45 plaques (32.8%). Superficial calcification and multiple such imaging techniques is limited. Eur Radiol Open Access This article is distributed under the terms of the Creative calcifications were observed more often in plaques with IPH Commons Attribution 4.0 International License (http:// and ulceration than those with neither IPH nor ulceration. creativecommons.org/licenses/by/4.0/), which permits unrestricted use, This study shows how detailed plaque characteristics may distribution, and reproduction in any medium, provided you give appro- associate with brain perfusion (Table 3). It was observed that priate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. patients with lesions containing IPH have lower CBF compared with those without. For patients with ulcerated carotid plaque, therewas alongerTTP andMMT in the ipsilateral infarction References area. Supporting this, the study found that patients with lesions with both IPH and ulceration had poorer brain perfusion in the 1. 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European RadiologySpringer Journals

Published: Jun 6, 2018

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