Linking quantitative radiology to molecular mechanism for improved vascular disease therapy selection and follow-up

Objective: Therapeutic advancements in atherosclerotic cardiovascular disease have improved the prevention of ischemic stroke and myocardial infarction. However, diagnostic methods for atherosclerotic plaque phenotyping to aid individualized therapy are lacking. In this thesis, we aimed to elucidate plaque biology through the analysis of computed-tomography angiography (CTA) with sufficient sensitivity and specificity to capture the differentiated drivers of the disease. We then aimed to use such data to calibrate a systems biology model of atherosclerosis with adequate granularity to be clinically relevant. Such development may be possible with computational modeling, but given, the multifactorial biology of atherosclerosis, modeling must be based on complete biological networks that capture protein-protein interactions estimated to drive disease progression.

Approach and Results: We employed machine intelligence using CTA paired with a molecular assay to determine cohort-level associations and individual patient predictions. Examples of predicted transcripts included ion transporters, cytokine receptors, and a number of microRNAs. Pathway analyses elucidated enrichment of several biological processes relevant to atherosclerosis and plaque pathophysiology. The ability of the models to predict plaque gene expression from CTAs was demonstrated using sequestered patients with transcriptomes of corresponding lesions. We further performed a case study exploring the relationship between biomechanical quantities and plaque morphology, indicating the ability to determine stress and strain from tissue characteristics. Further, we used a uniquely constituted plaque proteomic dataset to create a comprehensive systems biology disease model, which was finally used to simulate responses to different drug categories in individual patients. Individual patient response was simulated for intensive lipid-lowering, anti-inflammatory drugs, anti-diabetic, and combination therapy. Plaque tissue was collected from 18 patients with 6735 proteins at two locations per patient. 113 pathways were identified and included in the systems biology model of endothelial cells, vascular smooth muscle cells, macrophages, lymphocytes, and the integrated intima, altogether spanning 4411 proteins, demonstrating a range of 39-96% plaque instability. Simulations of drug responses varied in patients with initially unstable lesions from high (20%, on combination therapy) to marginal improvement, whereas patients with initially stable plaques showed generally less improvement, but importantly, variation across patients.

Conclusion: The results of this thesis show that atherosclerotic plaque phenotyping by multi-scale image analysis of conventional CTA can elucidate the molecular signatures that reflect atherosclerosis. We further showed that calibrated system biology models may be used to simulate drug response in terms of atherosclerotic plaque instability at the individual level, providing a potential strategy for improved personalized management of patients with cardiovascular disease. These results hold promise for optimized and personalized therapy in the prevention of myocardial infarction and ischemic stroke, which warrants further investigations in larger cohorts.

List of scientific papers

I. Karlöf E, Buckler AJ, L. Liljeqvist M, Lengquist M, Kronqvist M, Toonsi MA, Maegdefessel L, Matic L, Hedin U. Carotid Plaque Phenotyping by Correlating Plaque Morphology from Computed Tomography Angiography with Transcriptional Profiling. European Journal of Vascular and Endovascular Surgery. Volume 62, Issue 5, 2021, Pages 716-726.
https://doi.org/10.1016/j.ejvs.2021.07.011

II. Buckler AJ, Karlöf E, Lengquist M, Gasser TC, Maegdefessel L, Matic L, Hedin U. Virtual Transcriptomics: Noninvasive Phenotyping of Atherosclerosis by Decoding Plaque Biology From Computed Tomography Imaging. Arteriosclerosis, Thrombosis, and Vascular Biology. Vol. 41, No. 5, May 2021.
https://doi.org/10.1161/ATVBAHA.121.315969

III. Buckler AJ, Wanrooij MV, Andersson M, Karlöf E, Matic L, Hedin U, Gasser TC. Patient-Specific Biomechanical Analysis of the Fibrous Cap is Enabled by Histologically Validated Tissue Characterization by CTA: A Case Study. [Accepted]
https://doi.org/10.1016/j.jmbbm.2022.105403

IV. Buckler AJ, Marlevi D, Skenteris NT, Matic L, Hedin U. In Silico Model of Atherosclerosis with Individual Patient Calibration to Enable Precision Medicine for Cardiovascular Disease. [Manuscript]