Assessment of Attenuation in Pericarotid Fat among Patients with Carotid Plaque and Spontaneous Carotid Dissection ================================================================================================================== * Mohammed O. Alalfi * Riccardo Cau * Giovanni Maria Argiolas * Roberta Scicolone * Cesare Mantini * Valentina Nardi * John C. Benson * Jasjit S. Suri * Zafer Keser * Amir Lerman * Giuseppe Lanzino * Paolo Siotto * Luca Saba ## Graphical Abstract ![Figure1](http://www.ajnr.org/https://ajnr-sso.highwirestaging.com/content/ajnr/46/2/259/F1.medium.gif) [Figure1](http://www.ajnr.org/content/46/2/259/F1) ## Abstract **BACKGROUND AND PURPOSE:** Changes in perivascular fat density (PFD) and its association with inflammation have been topics of interest in both atherosclerotic and nonatherosclerotic vasculopathies. The objective of this study was to assess the PFD in patients with spontaneous internal carotid artery dissection (SICAD) or carotid atherosclerotic plaque, with and without intraplaque hemorrhage (IPH). **MATERIALS AND METHODS:** A cross-sectional retrospective bicentric analysis of 130 patients (30 with SICAD and 100 with carotid atherosclerotic plaque) who underwent CT angiography was performed. Among the subjects with atherosclerotic plaque, 36 showed the presence of IPH. PFD analysis was performed by 2 radiologists who placed 2 ROIs to identify the perivascular fat tissue attenuation. The Mann-Whitney *U* test was conducted to evaluate the difference between patient cohorts. **RESULTS:** Carotid arteries with SICAD and IPH demonstrated an average PFD of −68.97 HU (95% CI, −72.11 to −65.82 HU) and −69.97 HU (95% CI, −73.00 to −66.95 HU), respectively, in comparison with patients without IPH, who showed an average PFD −77.11 HU (95% CI,−78.78 to −75.44 HU) (*P* < .001 for both). Conversely, no significant differences were found between patients with SICAD and those with carotid plaque with IPH (*P* = .324). **CONCLUSIONS:** The average PFDs in patients with SICAD and carotid atherosclerosis plaque with IPH were similar and higher than those in patients with carotid plaque without IPH. This finding suggests a shared pathologic inflammatory mechanism in these 2 conditions. Studies comparing pathologic specimens directly with radiologic images may be needed to confirm this indirect hypothesis. ## ABBREVIATIONS: ICC : intraclass correlation coefficient IPH : intraplaque hemorrhage PFD : perivascular fat density SICAD : spontaneous internal carotid artery dissection The assessment of attenuation in pericarotid fat among patients with carotid atherosclerotic plaque and spontaneous carotid dissection has become an increasingly relevant topic in vascular medicine and neuroradiology. This interest is increased by emerging evidence linking perivascular fat density (PFD) with the presence and characteristics of atherosclerotic plaques,1⇓⇓-4 which are critical in the pathogenesis of cerebrovascular events.1 The research in this area, bridging the gap between advanced imaging techniques and clinical outcomes, offers valuable insight into the noninvasive identification and assessment of high-risk vascular conditions. Recent studies have shown a correlation among perivascular fat inflammation, carotid plaque vulnerability, and cerebrovascular events. Similarly, another study showed a significant correlation between PFD and contrast plaque enhancement on CTA, a marker of vulnerable carotid plaque.2 These findings, derived from a retrospective analysis of 100 patients, indicate that higher PFD is associated with plaque instability, particularly in symptomatic patients. Baradaran et al1 explored the association between carotid artery PFD and cerebrovascular ischemic events. Through a meticulous analysis of CTA examinations in patients with ICA stenosis, their work underlined the role of increased PFD as a surrogate marker for perivascular inflammation, particularly in those with stroke or TIA. Additionally, growing evidence also demonstrated a role for pericarotid fat in nonatherosclerosis carotid diseases. Cheng et al5 explored changes in PFD in a cohort of patients with spontaneous internal carotid artery dissection (SICAD), demonstrating higher PFD values in patients with carotid artery dissection compared with those without it. Including patients with dissection allows us to investigate whether similar pathophysiologic mechanisms involving inflammation and PFD changes are at play in both atherosclerotic and nonatherosclerotic carotid conditions. Understanding these mechanisms could offer new insight into the management and risk stratification of patients with diverse carotid pathologies. Among the features of vulnerability, intraplaque hemorrhage (IPH) is considered one of the most severe and could represent a subcategory of features of vulnerability related to the local inflammation that could alter the PFD.6⇓-8 Therefore, the purpose of this study was to investigate the association between PFD values in patients with SICAD and carotid atherosclerosis with and without IPH. ## MATERIALS AND METHODS ### Study Design and Patient Population This study was an observational cross-sectional cohort study conducted in 2 centers (AOU Cagliari and AO Brotzu). Institutional review board approval was obtained, and informed consent waived because of its retrospective nature. This study was conducted in accordance with STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines for cross-sectional studies. The cohort of patients with carotid atherosclerotic disease comprised consecutive adult subjects who underwent CTA for suspected atherosclerotic disease of the carotid arteries from May 2019 to March 2020 (Fig 1). Patients with acute ischemic stroke secondary to ipsilateral carotid disease were included, whereas patients with alternative stroke etiologies were excluded. Exclusion criteria were the following: subjects younger than 18 years of age; CTAs performed for reasons other than suspected atherosclerotic disease (ie, dissection); and other etiologies for ischemic stroke such as evidence of a cardiac embolic source (fibrillation, endocarditis), evidence of embolism from the thoracic aorta, and evidence of vertebrobasilar artery disease. Moreover, those with the presence of known pathologies of the arterial wall (collagenopathies such as Marfan syndrome and inflammatory conditions) and patients with a history of major neck surgeries and radiation therapy to the neck were also excluded. ![FIG 1.](http://www.ajnr.org/https://ajnr-sso.highwirestaging.com/content/ajnr/46/2/259/F2.medium.gif) [FIG 1.](http://www.ajnr.org/content/46/2/259/F2) FIG 1. Flow chart of the SICAD and atherosclerotic patient recruitment. The presence of IPH using CTA was calculated using the model suggested by Saba et al9 (threshold of <25 HU). Patients with SICAD were those who had evidence of acute carotid dissection on imaging (CTA with MRI confirmation) in the absence of any traumatic events (both minor and major trauma) in their medical history. The exclusion criteria were subjects younger than 18 years of age and the presence of known pathologies of the arterial wall (collagenopathies such as Marfan syndrome and inflammatory conditions). Patients with history of major neck surgeries, radiation therapy to the neck, and active bloodstream infections like endocarditis were also excluded. Patients with a concomitant atherosclerotic process (considered as a plaque determining a degree of stenosis of >50%) ipsilateral to the SICAD were excluded. These cases were selected from April 2015 to October 2022 in 2 different centers (Azienda Ospedaliero Universitaria, di Cagliari, Cagliari, Italy, and ARNAS Brotzu Hospital, Cagliari, Italy). A patient was considered symptomatic when he or she had a TIA or stroke. In this study, we considered 3 months the time window to be included in the symptomatic group. ### CTA Technique CTA of the carotid arteries was performed with multiple scanner technologies according to a standardized protocol. None of the patients who underwent CTA of the carotid arteries had a medical history of cardiac output failure or contraindications to iodinated contrast media. The patients were positioned supine with their heads inclined backwards to avoid dental artifacts. Scanning coverage extended from the aortic arch to the carotid siphon, proceeding in a caudocranial direction. Scans were obtained both pre- and post-contrast administration. For the angiographic phase, a preheated contrast medium was used, injecting 40–60 mL at a rate of 4–5 mL/s. To determine the optimal scan timing, we used a bolus-tracking technique. Dynamic monitoring scanning commenced 6 seconds after the start of the IV contrast injection. Inside the ROI, the trigger threshold was set at +80 HU over the baseline. There was a 1-second interval between each monitoring scan acquisition. On reaching the threshold, patients were instructed to hold their breath. After a 4-second interval, scanning in the caudocranial direction began. CT technical parameters included the following: matrix, 512 × 512; field of view, 14–19 cm; 180–250 mAs; 120 kV. A convolution filter algorithm was applied. Interactive window/level settings were usually set at W 850:L 300, progressing to very wide settings in the case of attenuated hyper dense calcifications.10 ### Carotid Plaque Analysis Hounsfield unit measurements were performed by 2 radiologists in consensus. The data sets were assessed in a circular or elliptical ROI (≥1 mm2) in the predominant area of the plaque to measure the Hounsfield units.11 Areas showing contamination by contrast material or calcifications and regions of beam-hardening were excluded. In cases in which 50% of the plaque contained calcium components, we considered the plaque calcified. ### Analysis of Perivascular Fat Attenuation Two radiologists, in consensus, conducted the PFD analysis using a previously validated method.1,2 To identify the fat tissue area, the 2 radiologists chose the ROIs, and each ROI measured at least 2.5 mm2 and was placed on the perivascular fat seen on the same axial slice that showed the highest degree of ICA stenosis as defined by the North American Symptomatic Carotid Endarterectomy Trial (NASCET; [https://pubmed.ncbi.nlm.nih.gov/2057968/](https://pubmed.ncbi.nlm.nih.gov/2057968/)) (Fig 2). Postcontrast scans were used for the analysis. The values obtained from these 2 ROIs were then averaged. ![FIG 2.](http://www.ajnr.org/https://ajnr-sso.highwirestaging.com/content/ajnr/46/2/259/F3.medium.gif) [FIG 2.](http://www.ajnr.org/content/46/2/259/F3) FIG 2. Examples of pericarotid fat measurement in a subject with SICAD (*A*), showing a value of 69 HU, with an atherosclerotic plaque with IPH (*B*), where a value of 70 HU can be observed, and with an atherosclerotic plaque without IPH (*C*), where a value of 80 HU can be observed. ### Statistical Analysis The suitability of each group of continuous variables for normal distribution was assessed with the Kolmogorov-Smirnov *Z*-test. We represented continuous data as mean (SD), while binary variables were presented as count and percentage. To determine the relationship in patients between PFD and carotid plaque (with and without IPH), we computed Pearson ρ product moment correlation coefficients. To compare these ρ correlation values, we used the Fisher r-to-z transformation. Additionally, the Mann-Whitney *U* test was conducted to evaluate the differences between groups. The intraclass correlation coefficient (ICC) was calculated for the PFD analysis in 40 patients (20 with SICAD and 20 with atherosclerotic plaques). Statistical significance was considered for *P* values < .05, and all correlation analyses were based on a 2-tailed significance level. For all statistical calculations, R software ([www.r-project.org](http://www.r-project.org)) was used. ## RESULTS ### Baseline Characteristics Of a cohort of 130 patients, 30 patients had SICAD (Center A contributed 9 cases of SICAD and Center B contributed 21 cases of SICAD), while 100 patients (all subjects from the center A) had carotid atherosclerotic plaque. Thirty-six patients of 100 (36%) showed IPH. Baseline demographic characteristics are summarized in Table 1. In patients with SICAD, the median time interval between symptoms and events was 18 hours (range, 3 hours to 6 days), whereas in non-SICAD symptomatic patients, the median time between symptoms and events was 31 hours (range, 3 hours to 18 days), with a statistically significant difference (*P* < .001). View this table: [Table 1:](http://www.ajnr.org/content/46/2/259/T1) Table 1: Baseline characteristics ### Perivascular Fat Attenuation in Carotid Artery Dissection versus Carotid Plaque In patients with carotid atherosclerotic plaque (both with and without IPH, *n* = 100), the average PFD was −74.54 HU (95% CI, −76.18 to −72.9 HU), while the average PFD in patients with SICAD was −68.97 HU (95% CI, −72.11 to −65.82 HU) (*P* < .001). Figure 3 illustrates the difference in PFD between patient groups with SICAD and carotid plaque. ![FIG 3.](http://www.ajnr.org/https://ajnr-sso.highwirestaging.com/content/ajnr/46/2/259/F4.medium.gif) [FIG 3.](http://www.ajnr.org/content/46/2/259/F4) FIG 3. Histograms and boxplots illustrating the difference of PFD value in patients with atherosclerosis and SICAD. Patients with atherosclerosis with no IPH had lower PFD values than those with IPH and SICAD. Patients with SICAD and IPH had relatively close values. In the patient group with carotid atherosclerotic plaque (*n* = 100), 36 patients demonstrated the presence of IPH and had a mean PFD value of −69.97 HU (95% CI, −73.00 to −66.95 HU). Patients without IPH (*n* = 64) had a more negative PFD value of −77.11 HU (95% CI, −78.78 to −75.44 HU) (*P* < .001). A plot demonstrating the relationship of PFD in patients with uncomplicated carotid plaque versus patients with carotid plaque complicated by IPH is shown in Fig 3. Finally, further analysis showed that the PFD value of patients with IPH was very similar (average value of −69.97 HU [95% CI, −73.00 to −66.95 HU]) compared with the PFD value of patients with SICAD (average value of −68.97 HU [95%, CI, −72.11 to −65.82 HU]) (*P* = .324). Figure 3 shows the PFD values for SICAD and carotid plaque with IPH. Mann-Whitney analysis demonstrated a statistically significant difference in PFD according to the disease in question as shown in Table 2. View this table: [Table 2:](http://www.ajnr.org/content/46/2/259/T2) Table 2: Mann-Whitney *U* Test Table 3 summarizes the PFD values depending on the different groups. The ICC analysis performed in the sample of 40 cases showed a value of 0.893, which can be considered good reliability. View this table: [Table 3:](http://www.ajnr.org/content/46/2/259/T3) Table 3: PFD values of carotid plaque versus SICAD ## DISCUSSION This study hypothesizes that changes in PFD are associated with inflammatory processes in both atherosclerotic and nonatherosclerotic carotid diseases, specifically SICAD and carotid atherosclerotic plaque with IPH. The central premise is that increased PFD is an indicator of inflammation that may contribute to the pathogenesis and progression of these 2 conditions, potentially serving as a noninvasive marker for identifying high-risk vascular conditions. In our cohort study of 130 patients, the mean PFD value in the patient group with SICAD was higher than that in patients with carotid atherosclerotic plaque without IPH (*P* < .001), while it was nearly equivalent to that in the group with IPH (*P* = .324). These findings suggest the presence of a higher level of inflammation in the perivascular fat of both patients with SICAD and carotid plaque with IPH. The value of PFD and its association with vascular pathology is an increasing topic of interest, and its value has been demonstrated in different organs such as pericarotid and periaortic attenuation.12⇓-14 It is well-demonstrated in the literature that there is a complex and bidirectional crosstalk between the vascular wall and the surrounding perivascular adipose tissue.15 Therefore, it is plausible for perivascular fat attenuation to serve as a surrogate marker of inflammation. The etiology of SICAD is complex and not completely understood, but it is hypothesized that several factors interplay, including genetic predisposition and environmental triggers such as infection.16,17 The hypothesis is that underlying constitutional weakness of the vessel wall in patients with SICAD is genetically determined and that environmental factors such as acute infection could trigger it.18 The likely common denominator between these complex etiologies could be the role of inflammation.5,19 In a retrospective analysis of 29 patients, 18 with SICAD, Naggara et al20 demonstrated the association between inflammation and SICAD by showing the presence of periarterial edema using cervical high-resolution MR imaging and elevated acute phase reactants such as the erythrocyte sedimentation rate and C-reactive protein. However, serum inflammatory markers were unable to pinpoint the specific location of vascular inflammation.21,22 Other authors have reinforced the role of imaging to detect inflammation-induced changes in perivascular carotid fat tissue in patients with carotid and coronary dissection.5,23 In a study by Pfefferkorn et al,24 increased [18F] FDG accumulation on PET/CT and perivascular contrast enhancement on high-resolution MRI, respectively, were found in patients with SICAD, suggesting vessel wall inflammation in patients experiencing an acute carotid dissection. The attenuation alteration in the periarterial fat is demonstrated in the coronary arteries, where the variation of attenuation in the fat is considered an indirect parameter of coronary plaque inflammation.25 Our findings are in line with these hypotheses suggesting a strong correlation between SICAD and inflammation as demonstrated by the presence of a more positive PFD compared with patients with uncomplicated carotid plaque (*P* < .001) and also consistent with the findings of Cheng et al.5 Given the cross-sectional nature of our study, we can show only an association, and further studies are needed to establish a potential causation between the inflammation and SICAD. If there is any causation, its directionality (inflammatory state leading to an instability in the blood vessel, thus a dissection versus blood vessel rupture and intramural hematoma causing perivascular inflammation) will also be crucial to determine. Similarly, inflammation is recognized as a significant contributor to atherosclerotic plaque formation and progression, and pericarotid fat contributes to promoting atherosclerosis through its bidirectional cross-talk between the vascular wall.1,2 IPH is a well-known biomarker of plaque vulnerability.26⇓⇓-29 The available body of literature discussing the relationship between IPH and PFD is scarce3,4 but, nevertheless, supports the idea of the presence of high PFD in patients with IPH. Our findings support this claim by demonstrating a more positive PFD value compared with patients with uncomplicated carotid plaque (*P* < .001) and are concordant with those of Yu et al,4 who found that PFD was significantly associated with high-risk American Heart Association lesion type VI plaque characterization and IPH. A key point of this article was identifying plaque with IPH to assess the characteristics of the pericarotid fat. It is widely demonstrated that MRI is the imaging-based criterion standard for IPH identification, but some recent evidence has shown that CT also offers good performance. In particular, the threshold of 25 HU for identifying plaque with IPH was chosen on the basis of the publication by Saba et al.9 The authors found that using 25 HU, the receiver operating characteristic analysis showed a sensitivity of 93.22% and a specificity of 92.73%. Our findings of altered PFD in patients with both SICAD and IPH could suggest an overlap between the inflammatory pathways of these entities. In vulnerable plaques, the interconnected pathways between the vessel wall and pericarotid fat release inflammatory cytokines, resulting in heightened vascular oxidation and inflammation. Consequently, this process increases microvascular permeability, potentially contributing to the subsequent rupture of intraplaque neovessels.4 Most interesting, similar mechanisms have been proposed in arterial dissection.5,30⇓-32 Arterial dissection is characterized by an intramural hematoma and/or a dissected intimal layer, with a complex and multifaceted pathogenesis, potentially involving vasa vasorum and vascular smooth-muscle cell proliferation.33,34 In this scenario, dysfunctional perivascular fat can promote endothelial dysfunction, vascular smooth-muscle cell proliferation, and vasa vasorum proliferation and rupture,35 consequently leading to arterial dissection.34 Clinically, recognizing a link between IPH and SICAD could enhance our understanding of the inflammatory mechanisms underlying carotid artery diseases. By establishing a link between PFD and vascular inflammation, we could improve risk stratification for patients with SICAD and carotid atherosclerosis. Additionally, these insights might lead to the development of targeted interventions to stabilize vulnerable plaques and prevent adverse cerebrovascular events, thereby reducing the burden of stroke and other complications related to carotid artery diseases. Lifestyle modifications, aggressive risk factor control, and anti-inflammatory medications may emerge as key interventions to stabilize vulnerable arterial walls and reduce plaque instability across these conditions. Currently, there is no proven therapy to prevent SICAD. Furthermore, when comparing the repeatability and complexity of the other imaging methods, MRI vessel wall imaging is highly accurate and provides detailed visualization of the pericarotid fat due to the assessment of the signal intensities, yet it can be time-consuming and expensive. In contrast, ultrasound is more accessible and cost-effective, offering real-time assessments, but interpretation may be more operator-dependent and less repeatable across different settings. We acknowledge several limitations in our study. First, due to the retrospective nature of our study and the small patient cohorts, our findings need validation in a larger prospective analysis. SICAD represents a very challenging subgroup, highly dependent on an accurate medical history, which can be suboptimal in a retrospective approach. Second, the use of different CT scanners in a relatively long timeframe could have introduced a technologic bias related to the energy level (milliampere-seconds and care dose systems with amperage modulation) used that may have an impact on the Hounsfield unit attenuation values. The third point is related to the method of attenuation measurements on CT, by which confounding factors and inaccuracies may affect the results, in particular, the variability in ROI placement, the involved segment possibly being much longer than 1 slice, and patients with a small amount of pericarotid fat. The fourth point is related to the absence of assessment of intracranial stenosis, presenting a potential confounding factor. A further point is related to IPH detection with CTA, which can present some bias due to the Hounsfield unit overlap between blood and lipid/fibrous tissue. The last point concerns the 3-month time window used to consider patients as symptomatic: This is a long interval and could have introduced potential bias in terms of variation in the degree of inflammation in the pericarotid fat. ## CONCLUSIONS In patients with SICAD and IPH, changes in perivascular carotid fat tissue are found, suggesting a common pathologic inflammation pathway in these 2 entities. 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