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Biomarkers of High-Risk Carotid Atherosclerosis

  • Author / Creator
    Kamtchum Tatuene, Joseph
  • Carotid atherosclerosis is responsible for 15-25% of the nearly 8 million first-ever ischemic strokes that occur each year worldwide. This proportion has remained constant over the past three decades, thus suggesting that some patients with carotid atherosclerosis currently receive suboptimal treatment to prevent stroke. Therefore, new strategies are needed not only to improve stroke risk stratification but also to better understand the pathobiology of carotid atherosclerosis. The overall objective of this three-part doctoral thesis was to provide new robust evidence to support the use of both imaging and blood biomarkers for clinical decision-making in the routine management of patients with carotid atherosclerosis.

    In the first part of our work, we used a meta-analysis approach to demonstrate that ipsilateral non-stenotic carotid plaques with high-risk imaging features are common in patients with embolic stroke of unknown source and might be the actual cause of the stroke. We relied on the same approach to show that high-risk plaques are common in asymptomatic carotid stenosis and the associated risk of ipsilateral ischemic cerebrovascular events is higher than commonly perceived. In the second part, we conducted systematic literature reviews and identified several biomarkers that have been associated with carotid plaque vulnerability or progression and with cerebrovascular events in patients with carotid atherosclerosis. Such biomarkers included interleukin-1β, interleukin-6, C-reactive protein, uric acid, lipoprotein-associated phospholipase A2, and lectin-like oxidized LDL receptor among others. However, none of the biomarkers had a validated threshold for use in the clinical management of patients with carotid atherosclerosis and only a few were targetable with existing drugs, notably interleukin-6. In the third part, we used a prediction modelling approach to demonstrate that interleukin-6 predicts carotid plaque severity, vulnerability, and progression, independent of dyslipidemia and other cardiovascular risk factors. We also showed that 2.0 pg/mL represents a promising candidate clinical cut-off that could help select patients with carotid atherosclerosis who would benefit from anti-IL6 drugs as an adjuvant stroke prevention strategy. Furthermore, we provided preliminary evidence that monocyte transcriptomics analysis could help define a distinctive molecular profile for high-risk carotid atherosclerosis to inform in-depth pathobiological investigations and potentially support the identification of new biomarkers and therapeutic targets.

    Altogether, our research has four core implications for clinical practice and research. First, routine assessment of carotid atherosclerosis beyond the grade of stenosis using multimodal neurovascular imaging should be implemented in clinical practice to support the etiological classification of embolic strokes of unknown source, improve stroke risk stratification in asymptomatic carotid stenosis, and optimize stroke prevention strategies. Second, revascularization trials using multimodal neurovascular imaging for risk stratification before randomization in patients with asymptomatic carotid stenosis are warranted. Third, biomarkers have a role to play in the management of carotid atherosclerosis, but more research is needed to accelerate their integration into routine clinical practice, notably the definition and validation of thresholds, the combination into panels, and the integration into diagnostic and prognostic tools. Finally, trials of anti-interleukin-6 drugs as an adjuvant stroke prevention strategy in people with carotid atherosclerosis are warranted.

  • Subjects / Keywords
  • Graduation date
    Spring 2022
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/r3-ft2k-b738
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.