Integrative investigation of retinal vascular complexity and its application for cardiovascular disease
Creators: name: Villaplana Velasco, Ana
Publisher: name: The University of Edinburgh
Year: 2023
Subjects: Retinal Vascular Complexity
Cardiovascular Disease
noninvasive biomarker
fatal cardiovascular events
cardiovascular predictive models

description: The early detection of cardiovascular events is a key strategy for controlling and reducing their leading and increasing morbidity and mortality worldwide. The integration of novel technological and scientific advances has been central for early identifying the pathogenesis of these multifactorial diseases, and this is certainly the case of the retina. The retina is the innermost layer of the eye unique in allowing the observation of the vascular system in vivo using non-invasive imaging modalities. By implementing semi-automated scoring, retinal images can provide phenotypes that capture the structure of the vascular network, such as the branching pattern. The branching pattern, also named retinal vascular complexity, is an unexplored trait of the retinal vasculature that captures the degree of intricacy and branching complexity of the entire plexus. This trait then can quantify subtle variations within the network, making it an optimal phenotype for investigating morphological variation within the retinal plexus. There is increasing evidence that retinal vascular complexity could offer earlier insight into the progression of major cardiovascular diseases than established risk factors. Thus, retinal vascular complexity could be a promising noninvasive biomarker for fatal cardiovascular events, such as myocardial infarction and stroke. Multiple efforts have integrated this phenotype into cardiovascular predictive models but have not translated so far into a substantial prediction improvement when compared to established models based on demographic and clinical variables. Population-based studies demonstrated that retinal vascular phenotypes different from vascular complexity have a genetic basis, where associated loci also contribute to cardiovascular physiology and pathology. This suggests a shared genetic basis between the retinal and global vascular systems during early ischaemic stages, contributing to similar pathophysiological variations. However, there is little information about the genetic component that underlies the retinal vascular complexity and little is known about the additional predictive value of this trait for predicting fatal vascular events. Elucidating its genetic architecture and its predictive value are then of great importance, as it could lead to a better understanding of the regulation of retinal and major vascular systems and, consequently, substantiate the future application of retinal vascular complexity as a biomarker of systemic vascular health. This thesis aims to comprehensively analyse retinal vascular complexity by integrating epidemiological, genetic, and translational disciplines. To this end, we obtained retinal vascular complexity from retinal fundus images and demographic, clinical, and genotyping information from approximately 38,800 participants with white-British ancestry in the UK Biobank. Exploratory analyses revealed that retinal vascular complexity is associated with image quality, age, sex, ocular, and cardiovascular traits and conditions. We found that decreased vascular complexity is associated with a higher risk of myocardial infarction and stroke, independently of established risk factors. Furthermore, we found nine independent loci after finemapping (rs73175105 in chromosome 3; rs16891982 in chromosome 5; rs12203592, and rs9375805 in chromosome 6; rs6018400 in chromosome 12; rs12913832, rs72714116, and rs58843292 in chromosome 15; and rs73226964 in chromosome 21) located near EIF2B5, SLC45A2, IRF4, RDH5, HERC2, OCA2, and AGPAT3 genes contributing to retinal vascular complexity that were previously reported in genetic studies of ocular and cardiovascular disease. Functional and enrichment analyses indicated that three of these loci (rs16891982, rs12203592, and rs12913832) regulate NOTCH and VEGF transcriptional signalling activity, which are central mechanisms to the development and physiology of the retinal vasculature and influence global vascular pathology. Finally, we characterised the predictive value of retinal vascular complexity in ischaemic risk through the development of separate predictive strategies for coronary artery disease, myocardial infarction, and stroke. We observed that our predictive models including retinal vascular complexity and a disease-specific polygenic risk score achieved a greater perfomance when compared with a reproduction of established baseline models (AUCMI = 0.770±0.0013 vs AUCMI−Baseline = 0.711±0.0021, AUCCAD = 0.763±0.0018 vs AUCCAD−Baseline = 0.713±0.0021, and AUCSTR = 0.690±0.0015 vs AUCSTR−Baseline = 0.639±0.0025). Further analyses on our proposed models revealed that Df and the polygenic risk score captured an early predictive value for these conditions not fully reflected in clinical variables, resulting in a more accurate and earlier risk stratification. Overall, this study was the first to date to delve into the genetic component of retinal vascular complexity, describing part of its genetic mechanisms and its association with global vascular genetics, and exploring its application in the stratification of ischaemic risk. Our findings are consistent with previous reports, suggesting that retinal vascular complexity has an intricate shared genetic basis with cardiovascular conditions. Furthermore, our observations indicate that predictive models that leverage retinal vascular complexity could be clinical opportune systems to early identify individuals at high risk of major ischaemic events. This thesis ultimately sheds new light on the value of highly accessible vascular imaging phenotypes and their promising application in personalised medicine.