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Interrogating Atherosclerotic Plaque Biology Through Responses to Cardiovascular Risk Management and Imaging
Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart Center, Department of Cardiology in Linköping.ORCID iD: 0000-0002-3418-1706
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Atherosclerosis causes more deaths than any other disease worldwide, and the cause of death is most commonly a rupture of a vulnerable atherosclerotic plaque, resulting in a thrombotic event in the heart or brain. The major risk factors for plaque progression are well known, but all the mechanisms that drive atherosclerotic plaques towards catastrophic events are not yet fully elucidated.   

This thesis revolves around the atherosclerotic plaque; how plaques can be analysed using cardiovascular magnetic resonance imaging and the study of biological responses to cardiovascular risk management. In Study I we interrogated the quality of cardiovascular risk management in patients diagnosed with high-grade carotid stenosis and found that cardiovascular risk management was deficient in all aspects, despite the very high risk for events in these patients. Thus, we designed the next two studies to address the unmet clinical need for improved cardiovascular risk management in patients with carotid atherosclerosis while at the same time asking mechanistic questions about the effect of this approach on lymphocyte phenotypes (Study II) and on plaque composition (Study III).  

In Study II, the effect of cardiovascular risk management on Natural Killer cell, Natural Killer T cell and T lymphocyte subpopulations were studied in patients with carotid atherosclerosis. Our results show a polarisation away from a senescent phenotype towards more naïve i.e., juvenile cell types suggesting a transition towards a possibly less pro-inflammatory lymphocyte profile.   

In Study III, we applied a newly developed quantitative Dixon MRI technique to the quantification of lipid rich necrotic core and hemorrhage inside atherosclerotic plaques. Employing this technique, we explored the relationships between these high-risk plaque compositional features and circulating lipoproteins as they changed over time in response to cardiovascular risk management. In the current study there was no evidence for such a linear relationship.  

To further study the associations between inflammation and quantitative plaque measurements we explored in Study IV the relationship between inflammation in atherosclerotic plaques as measured by 18F-FDG uptake and features of high-risk plaque as measured by quantitative Dixon MRI.   

To facilitate the use of carotid MRI in larger cohorts we developed in Study V a technique for the segmentation of the carotid artery using supervised machine learning.   

Taken together these studies describe the importance of cardiovascular risk management, the complexity of atherosclerotic plaque biology and they propose new strategies for quantitative plaque imaging.   

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2023. , p. 90
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1833
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:liu:diva-190682DOI: 10.3384/9789179295660ISBN: 9789179295653 (print)ISBN: 9789179295660 (electronic)OAI: oai:DiVA.org:liu-190682DiVA, id: diva2:1720818
Public defence
2023-02-17, Berzeliussalen, Building 463, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2022-12-20 Created: 2022-12-20 Last updated: 2022-12-20Bibliographically approved
List of papers
1. High-grade carotid artery stenosis: A forgotten area in cardiovascular risk management
Open this publication in new window or tab >>High-grade carotid artery stenosis: A forgotten area in cardiovascular risk management
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2016 (English)In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 23, no 13, p. 1453-1460Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Patients with high-grade (≥70%) carotid artery stenosis (CAS) rank in the highest risk category for future cardiovascular (CV) events, but the quality of cardiovascular risk management in this patient group is unknown.

DESIGN: Cross-sectional retrospective study.

METHODS: Data were collected for all patients diagnosed with high-grade CAS in Östergötland county, Sweden between 1 January 2009 and 31 July 2012 regarding the quality of cardiovascular risk management, co-morbidity and outcomes during the 2-year follow-up period after a diagnosis of CAS with a carotid ultrasound scan. Patients were included regardless of whether they underwent carotid endarterectomy (CEA).

RESULTS: A total of 393 patients with CAS were included in the study; 133 (33.8%) underwent CEA and 260 (66.2%) were assigned to a conservative management (CM) group. In both groups of patients the prescription of platelet inhibitors, statins and antihypertensive drugs increased significantly (p < 0.001) after diagnosis. However treatment targets were not met in the majority of patients and the low-density lipoprotein level was on target in only 13.5% of patients. During follow-up, low-density lipoprotein levels were not measured in 19.8% of patients who underwent CEA and 44.2% of patients in the CM group (p < 0.001); HbA1c was not measured in 24.4% of patients with diabetes in the CEA group and in 18.8% of patients in the CM group (p = 0.560). There was no documentation of counselling on diet, exercise, smoking cessation or adherence to medication. The combined clinical event rate (all-cause mortality, cardiovascular mortality and non-fatal cardiovascular events) was high in both groups (CEA 36.8% and CM 36.9%; p = 1.00) with no difference in the occurrence of ipsilateral ischaemic stroke.

CONCLUSIONS: The clinical event rate was high in patients with high-grade CAS and the management of cardiovascular risk was deficient in all aspects.

Place, publisher, year, edition, pages
Sage Publications, 2016
Keywords
High-grade carotid stenosis, atherosclerosis, cardiovascular disease, cardiovascular risk management, secondary prevention
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-129961 (URN)10.1177/2047487316632629 (DOI)000382655100013 ()26879568 (PubMedID)
Note

Funding agencies. Linkoping University Hospital [LIO-417951]

Available from: 2016-07-02 Created: 2016-07-02 Last updated: 2022-12-20Bibliographically approved
2. Quantitative Magnetic Resonance Imaging Assessment of the Relationships Between Fat Fraction and R2*Inside Carotid Plaques, and Circulating Lipoproteins
Open this publication in new window or tab >>Quantitative Magnetic Resonance Imaging Assessment of the Relationships Between Fat Fraction and R2*Inside Carotid Plaques, and Circulating Lipoproteins
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2022 (English)In: Journal of Magnetic Resonance Imaging, ISSN 1053-1807, E-ISSN 1522-2586, Vol. 55, no 4, p. 1260-1270Article in journal (Refereed) Published
Abstract [en]

Background Lipid-rich necrotic core (LRNC) and intraplaque hemorrhage (IPH) are morphological features of high-risk atherosclerotic plaques. However, their relationship to circulating lipoproteins is unclear. Purpose To study associations between changes in lipoproteins vs. changes in LRNC (represented by fat fraction [FF]) and IPH (represented by R2*). Study Type Prospective. Subjects Fifty-two patients with carotid plaques, 33 males (63.5%), mean age 72 (+/- 5). Field Strength/Sequence Four-point fast gradient Dixon magnetic resonance imaging (MRI) was used to quantify FF and R2* (to measure IPH) inside plaques and in vessel wall. Turbo-spin echo was used for T-1 weighted sequences to guide manual segmentation. Assessment Carotid MRI and serum lipid levels were assessed at baseline and at 1-year follow-up. For patients, lipid-lowering therapy was customized to reduce low-density lipoprotein (LDL) levels below 1.8 mmol/L. Segmentation was performed with one set of regions of interest for the plaque and one for the vessel wall at the location of the plaque. Thereby MRI data for FF, R2*, and volumes in plaque- and vessel-wall segmentations could be obtained from baseline and follow-up, as well as changes over the study year. Statistical Tests Pearson correlation coefficient for correlations. Paired samples t-test for changes over time. Significance at P &lt; 0.05, 95% confidence interval. Results LDL decreased significantly (2.19-1.88 mmol/L, Z - 2.9), without correlation to changes in plaque composition, nor to the significant reduction in vessel-wall volume (-106.3 mm(3)). Plaque composition remained unchanged, FF +8.5% (P = 0.366) and R2* +3.5% (P = 0.304). Compared to plaque segmentations, R2* was significantly lower in the vessel-wall segmentations both at baseline (-9.3%) and at follow-up (-9.1%). Data Conclusion The absence of correlations between changes in lipoproteins and changes in plaque composition indicates more complex relationships between these parameters than previously anticipated. The significant differences in both R2* and volume dynamics comparing plaque segmentations and vessel-wall segmentations suggest differences in their pathobiology of atherosclerosis. Level of Evidence 1 Technical Efficacy Stage 4

Place, publisher, year, edition, pages
Wiley, 2022
Keywords
atherosclerosis; cardiovascular imaging; MRI; carotid plaques; lipoproteins
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-178459 (URN)10.1002/jmri.27890 (DOI)000684848000001 ()34390516 (PubMedID)
Note

Funding Agencies|Medical Research Council of Southeast Sweden (FORSS) [FORSS-756191]; Region ostergotland [Ro-696961, Ro-742821, Ro-803461, Ro-931539, Ro-700451, Ro-798681]

Available from: 2021-08-23 Created: 2021-08-23 Last updated: 2022-12-20
3. (18)Fluorodeoxyglucose uptake in relation to fat fraction and R2*in atherosclerotic plaques, using PET/MRI: a pilot study
Open this publication in new window or tab >>(18)Fluorodeoxyglucose uptake in relation to fat fraction and R2*in atherosclerotic plaques, using PET/MRI: a pilot study
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2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 14217Article in journal (Refereed) Published
Abstract [en]

Inflammation inside Atherosclerotic plaques represents a major pathophysiological process driving plaques towards rupture. Pre-clinical studies suggest a relationship between lipid rich necrotic core, intraplaque hemorrhage and inflammation, not previously explored in patients. Therefore, we designed a pilot study to investigate the feasibility of assessing the relationship between these plaque features in a quantitative manner using PET/MRI. In 12 patients with high-grade carotid stenosis the extent of lipid rich necrotic core and intraplaque hemorrhage was quantified from fat and R2* maps acquired with a previously validated 4-point Dixon MRI sequence in a stand-alone MRI. PET/MRI was used to measure F-18-FDG uptake. T1-weighted images from both scanners were used for registration of the quantitative Dixon data with the PET images. The plaques were heterogenous with respect to their volumes and composition. The mean values for the group were as follows: fat fraction (FF) 0.17% (0.07), R2* 47.6 s(-1) (+/- 10.9) and target-to-blood pool ratio (TBR) 1.49 (+/- 0.48). At group level the correlation between TBR and FFmean was - 0.406, p 0.19 and for TBR and R2*(mean) 0.259, p 0.42. The lack of correlation persisted when analysed on a patient-by-patient basis but the study was not powered to draw definitive conclusions. We show the feasibility of analysing the quantitative relationship between lipid rich necrotic cores, intraplaque haemorrhage and plaque inflammation. The F-18-FDG uptake for most patients was low. This may reflect the biological complexity of the plaques and technical aspects inherent to F-18-FDG measurements. Trial registration: ISRCTN, ISRCTN30673005. Registered 05 January 2021, retrospectively registered.

Place, publisher, year, edition, pages
Nature Research, 2021
National Category
Medical Image Processing
Identifiers
urn:nbn:se:liu:diva-178519 (URN)10.1038/s41598-021-93605-x (DOI)000674488400019 ()34244569 (PubMedID)
Note

Funding Agencies|Linkoping University; Henry och Ella Margareta Stahls Stiftelse (Henry and Ella Margareta Stahls Foundation) [LIO-748491]; Swedish HeartLung FoundationSwedish Heart-Lung Foundation [20170492]

Available from: 2021-08-25 Created: 2021-08-25 Last updated: 2022-12-20
4. Towards Automated Quantification of Vessel Wall Composition Using MRI
Open this publication in new window or tab >>Towards Automated Quantification of Vessel Wall Composition Using MRI
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2020 (English)In: Journal of Magnetic Resonance Imaging, ISSN 1053-1807, E-ISSN 1522-2586, Vol. 52, no 3, p. 710-719Article in journal (Refereed) Published
Abstract [en]

Background MRI can be used to generate fat fraction (FF) and R2* data, which have been previously shown to characterize the plaque compositional features lipid-rich necrotic core (LRNC) and intraplaque hemorrhage (IPH) in the carotid arteries (CAs). Previously, these data were extracted from CA plaques using time-consuming manual analyses. Purpose To design and demonstrate a method for segmenting the CA and extracting data describing the composition of the vessel wall. Study Type Prospective. Subjects 31 subjects from the Swedish CArdioPulmonary bioImage Study (SCAPIS). Field Strength/Sequences T-1-weighted (T1W) quadruple inversion recovery, contrast-enhanced MR angiography (CE-MRA), and 4-point Dixon data were acquired at 3T. Assessment The vessel lumen of the CA was automatically segmented using support vector machines (SVM) with CE-MRA data, and the vessel wall region was subsequently delineated. Automatically generated segmentations were quantitatively measured and three observers visually compared the segmentations to manual segmentations performed on T(1)w images. Dixon data were used to generate FF and R2* maps. Both manually and automatically generated segmentations of the CA and vessel wall were used to extract compositional data. Statistical Tests Two-tailedt-tests were used to examine differences between results generated using manual and automated analyses, and among different configurations of the automated method. Interobserver agreement was assessed with Fleiss kappa. Results Automated segmentation of the CA using SVM had a Dice score of 0.89 +/- 0.02 and true-positive ratio 0.93 +/- 0.03 when compared against ground truth, and median qualitative score of 4/5 when assessed visually by multiple observers. Vessel wall regions of 0.5 and 1 mm yielded compositional information similar to that gained from manual analyses. Using the 0.5 mm vessel wall region, the mean difference was 0.1 +/- 2.5% considering FF and 1.1 +/- 5.7[1/s] for R2*. Level of Evidence 1. Technical Efficacy Stage 1. J. Magn. Reson. Imaging 2020;52:710-719.

Place, publisher, year, edition, pages
WILEY, 2020
Keywords
atherosclerosis; plaque composition; segmentation; carotid arteries; magnetic resonance imaging; contrast-enhanced
National Category
Medical Image Processing
Identifiers
urn:nbn:se:liu:diva-168855 (URN)10.1002/jmri.27116 (DOI)000558373700005 ()32154973 (PubMedID)
Available from: 2020-09-11 Created: 2020-09-11 Last updated: 2022-12-20

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