Short summary

Ischemic stroke is a leading cause of disability and death globally. Atherosclerotic plaques in carotid arteries significantly affect stroke risk. Assessing plaque composition and atherosclerotic pathology is crucial. Inflammation in the vessel wall is key in atherosclerosis. This pilot study aims to: Develop a protocol for analyzing carotid PVAT via CT angiography. Investigate the relationship between plaque composition and carotid PVAT. Define PVAT differences and optimal cut-off values

Rationale

Background: Ischemic stroke remains a major cause of mortality and long-term disabilities. Despite the availability of advanced clinical tools like neuroimaging, acute stroke management, and secondary prevention measures, preventing stroke recurrence remains a challenging task. Large artery atherosclerosis (LAA) including the carotid artery, is a primary suspect in re-stroke. As a preventive treatment, carotid endarterectomy (CEA) has shown significant benefits in avoiding re-stroke for symptomatic patients with more than 50-70% carotid stenosis. However, there is a lack of comprehensive data concerning patients with mild to moderate stenosis who still face a risk of recurrence. The evaluation of plaque composition and atherosclerosis pathology in the carotid artery, rather than solely relying on the degree of stenosis, suggests a crucial consideration in developing prevention strategies. However, existing literature on this subject is limited. Inflammation plays a significant role in the pathogenesis of atherosclerosis and the formation of vulnerable atherosclerotic plaques. The cascade of inflammatory mechanisms within the arterial wall orchestrates a step-by-step progression, leading to the advancement of lesions and the subsequent development of stenotic regions. In this regard, perivascular adipose tissue (PVAT) attenuation in the coronary arteries has been shown to predict adverse cardiovascular outcomes in patients at risk of acute coronary artery disease PVAT harbors inflammatory reactions that may contribute to atherosclerosis within the vascular wall. According to Antoniades et al., PVAT seems to be involved in a bidirectional interplay with the vascular wall, involving various elements associated with vascular inflammation and oxidative stress. These signals result in increased edema and diminished adipocyte size. This may be crucial in forming the intravascular vulnerable plaques containing the essential features for identifying high-risk plaques. The proinflammatory pathways are initiated due to the physiological change in PVAT from lipid to aqueous phase. This change in attenuation can be estimated by Computed Tomography Angiography (CTA), where the change in attenuation can be analyzed based on changes in Hounsfield Units (HU). In the coronary arteries, a threshold of -70 HU in the perivascular Fat Attenuation Index (FAI) has been shown to indicate an increased risk of adverse cardiovascular outcomes. However, PVAT attenuation has not been examined in the carotid arteries before. Previous work indicates that patients with carotid plaque identified by ultrasound have adverse plaque features by CTA. In addition, intraplaque hemorrhage (IPH) and plaque volume in the carotid arteries may independently contribute to the risk of ipsilateral re-stroke, with PVAT playing a substantial role in the occurrence of IPH. Therefore, PVAT estimation and the measurement of FAI in the carotid vasculature could potentially serve as a predictive factor for re-stroke risk. If that is the case, HU of PVAT in the carotid artery of the side of stroke (culprit side) would tend to differ from the HU of PVAT on the other, non-culprit side, indicating less stable plaques on the culprit side. Integrating this knowledge together with stenosis grade and plaque composition would potentially improve the selection of patients for surgery or best medical treatment. Aim/Hypothesis The current research project has the following aims: 1. To develop a CTA-based protocol for analyzing PVAT in the carotid vasculature using a semi-automated PVAT quantification software, Autoplaque ©. 2. To examine the association between plaque composition and PVAT attenuation in the carotid arteries. 3. To examine the difference in PVAT attenuation between the culprit carotid artery and the non-culprit carotid artery in patients with stroke. The current study has the following hypotheses: - High PVAT attenuation in the carotid arteries correlates with the risk of ipsilateral stroke independently from the severity of stenosis. - Adverse carotid plaque features correlate with high carotid PVAT attenuation.

Description of the cohort

We will examine a cohort of patients who experienced their initial stroke in 2011 - 2017 and were under consideration for CEA, approximately N = 60. Patients in the age group 18 - 80 years old will be included in the study. Patients not eligible for surgical intervention will be excluded.

Data and biological material

. Data containing information on patient baseline and risk factors of stroke such as age, sex, tobacco use, lipids, blood pressure, comorbidities (diabetes mellitus, hypertension, hypercholesterolemia, and atrial fibrillation), medication and side of stroke will be recorded. The Danish Vascular Surgery database, a nationwide database, will be used to identify patients who underwent CT imaging at Aalborg University Hospital. Then, the data of relevance will be extracted from the journals of the patients and the list of National Health Register (LPR). Data will be extracted using the unique civil registration number, the CPR number. The data is passed on to the investigator. As such, the investigator does not have direct access the medical records. The preoperative CTA will be used for plaque composition and PVAT analyses. The PVAT attenuation on the culprit carotid artery will be compared with PVAT attenuation in the contralateral carotid artery. In addition, the carotid plaque composition in the culprit versus the non-culprit carotid arteries will be examined.

Collaborating researchers and departments

Department of Cardiology, Lillebaelt Hospital

• Ramshanker Ramanathan, senior registrar, postdoc

Department of Vascular Surgery, Lillebaelt Hospital

• Consultant and head of department, professorKim Christian Houlind

Department of Radiology, Lillebaelt Hospital

• Associate professor, Helle Precht

Department of Neurology, Lillebaelt Hospital

• Consultant and head of department, associate professor, Henrik Boye Jensen,

Cedars-Sinai Medical Center, Biomedical Imaging Research Institute, Los Angeles

• Professor, Damini Dey

Department of Vascular Surgery, Aalborg University Hospital

• Consultant and associate professor, Christian Nikolaj Petersen

Department of Neurology, Aalborg University Hospital

• Consultant, Boris Modrau

Department of Cardiology, Odense University Hospital

• Consultant and professor, Axel Cosmus Pyndt Diederichsen
• PhD-student, Selma Hasific