CARotid Mri of Atherosclerosis
CARotid Mri of Atherosclerosis
In the entire world most people die from cardiovascular disease. Death is primarily from
 myocardial infarction (MI) and stroke which are most often caused by rupture of
 atherosclerotic plaques. Patients with high-grade, i.e. ≥ 70% carotid artery stenosis are at
 especially high risk. Magnetic Resonance Imaging (MRI) studies show that two features inside
 plaques that are associated with the risk of plaque rupture and subsequent cardiovascular
 events are: lipid rich necrotic core (LRNC) and intraplaque hemorrhage (IPH).

 MRI studies on carotid artery plaques typically relies on proton-density-weighted fast-spin
 echo, blood-suppressed T1- and T2-weighted gradient-echo sequences. The end-result is
 nonquantitative measures, where plaque features are identified due to their relative signal
 intensity. To address these problems of non-specificity, we developed a quantitative MRI
 (qMRI) technique based on Dixon sequences.

 The study intention is to enable in-depth analysis of plaque features and their relation to
 clinical data. For example there is an insufficient understanding of associations between
 lipid biomarkers and plaque contents. Our hypothesis is that we can identify quantitative
 changes in both plaque and lipid biomarkers after one year of optimized cardiovascular risk
 management (including treatment with lipid lowering drugs), and establish if there is any
 associations between these features. Because there is a well-established link between
 systemic inflammation and the presence of atherosclerotic plaques we will also study the
 relationship between LRNC and IPH as measured by qMRI versus circulating markers of
 inflammation.

 Method: Patients with known carotid stenosis are invited for a baseline visit and a 1-year
 follow up visit. The study visits include clinical assessment, blood tests, patient interview
 and magnetic resonance imaging of the carotid arteries. All participants are offered
 optimized cardiovascular risk management through the individual assessment by the study
 physicians.
Regarding quality assurance plans that address data validation and registry procedures, the
 current study is a single centre investigator-initiated study and therefore there are no
 plans for site monitoring and auditing. The reliability and validity of the MRI data has been
 previously confirmed with comparison to 3D histology data (Koppal et al. Quantitative fat and
 R2* mapping in vivo to measure lipid-rich necrotic core and intraplaque hemorrhage in carotid
 atherosclerosis. Magn Reson Med. 2017;78(1):285-96.).

 Concerning data checks, intraobserver reliability regarding baseline and follow-up
 measurements will be ascertained (Intraclass Correlation Coefficients (ICC), Bland Altman).

 Data is collected from patient medical records (electronic), dedicated study record forms
 (paper) and clinical assessments, resulting in quantitative measures. These external data
 sources are transferred into a study database.

 The current study is a clinical study, using only clinically validated laboratory parameters.
 The source of the lab values and their normal ranges is the electronic patient record. The
 normal ranges have been established by the clinical chemistry and haematology laboratories at
 Linköping University Hospital. Clinical diagnosis and procedures are recorded using the
 International Classification of Diseases (ICD) classification.

 The study was approved by the Swedish Ethical Review Authority (approval nr: 2016-441-31) and
 performed in accordance with the Declaration of Helsinki. Written informed consent has been
 obtained from all study participants.

 Patients are selected based on duplex ultrasound criteria established for the European
 Carotid Surgery Trial. A cut-off at doppler flow velocity has been used to identify eligible
 patients and after considering inclusion and exclusion criteria patients have been contacted
 by the study clinicians dr Elin Good or dr Ebo de Muinck for recruitment. Any registration
 for adverse events follows the same procedures as in routine care.

 Sample size assessment was based on results from previous studies in relation to our primary
 outcome variables. For example, one study with 24 patients and a follow-up time of three
 months experienced a significant reduction of lipid rich necrotic core, using magnetic
 resonance imaging (Alkhalil et al. T2 mapping MRI technique quantifies carotid plaque lipid,
 and its depletion after statin initiation, following acute myocardial infarction.
 Atherosclerosis. 2018;279:100-6.). Therefore, we aimed to include 50 patients who have
 completed both baseline and follow-up, and the follow-up time was set to 12 months.

 Our plan for missing data in situations where variables are missing, unavailable,
 non-reported, uninterpretable etc is to not exclude the study participant, in order to avoid
 bias. For example, in cases where the imaging data from one patient is lost, we will still
 use the remaining clinical data from that patient if the patient has been included in the
 study.

 Regarding Statistical analysis, SPSS Statistics 26 (International Business Machines
 Corporation, New York, NY, USA) is used for statistical analysis. Continuous variables are
 summarized as mean ± standard deviation (SD). To address the primary objectives (the strength
 of the association between fat fraction (FF) and R2*) Pearson correlation coefficient is
 used, and Paired-samples T test is used for analysing changes in quantitative values between
 baseline and follow-up.

 Intra-observer repeatability measurements were calculated using ICC. For ICC evaluation we
 used two-way random effect models, checking for absolute agreement, average measures
 presented.
Inclusion Criteria:

 - Carotid plaques with a cut-off at doppler flow velocity ≥ 1.3 m/sec at a Doppler angle of
 50-60°, which corresponds to a ≥ 50% stenosis according to these criteria.

 Exclusion Criteria:

 -  Performed or planned carotid surgery

 -  Carotid occlusion

 -  Renal failure (GFR <45 ml/h)

 -  Inflammatory diseases, anti-inflammatory treatment or malignancies

 -  Stroke <30 days before admission

 -  Co-morbidities that disable informed consent or participation in the study
 investigations (e.g. contraindications for MRI)