title: Novel cardiovascular risk markers in cardiovascular diseases
Creators: name: Alghibiwi, Hanan
Publisher: name: University of Glasgow
Year: 2021

description: Introduction: Cardiovascular disease is the leading cause of death worldwide, and the global prevalence of cardiovascular disease increased every year. Cardiovascular disease (CVD) is a complex multifactorial disease. It is essential to understand the different biological and genetic factors that are associated with the development and progression of CVD in order to improve the diagnosis, prognosis and treatment of the condition and, thereby, reduce mortality and morbidity. The use of cardiometabolic markers, including blood biomarkers such as troponin, and NT-proBNP, as well as non-invasive imaging markers, such as carotid intima media thickness and pulse wave arterial stiffness, might help to correctly identify patients with a CVD risk at an early stage. These markers may help practitioners understand and monitor disease progression, but whether they provide additional information to the conventional risk factors included in the risk prediction model or disease progression is not currently clear. In contrast, other biomarkers could help provide insights into pathophysiological processes and help practitioners understand potential drug targets. MicroRNAs (miRNAs) are a family of small, noncoding RNA molecules that regulate gene expression by targeting specific messenger RNA. Dysregulation of specific miRNAs expression have been associated with cardiovascular diseases. Since the discovery of miRNAs in body fluids, including plasma, saliva and urine, a strong body of evidence has been published demonstrating the potential use of circulating miRNAs as markers for several diseases, including CVD. This thesis studies the possible determinants for imaging markers of cardiovascular disease risk, including carotid intima media thickness and pulse wave arterial stiffness index and further investigates putative circulating miRNAs as novel biomarkers for cardiovascular diseases. The overarching aim is to provide insight into novel biomarkers for monitoring and treatment of cardiovascular disease progression. The associations of circulating miRNA expression with markers of cardiometabolic diseases: CAMERA trial: Candidate circulating miRNAs were selected on the basis of the findings in the literature review that showed that their dysregulation was associated with a change of cardiometabolic markers such as cardiac enzyme and imaging markers. A cross-sectional analysis was conducted to investigate the associations of circulating miRNAs, miR30c, miR103, miR133a, miR122 and miR146a with cardiometabolic markers, using 60 paired stored plasma samples at baseline and after 18 months from the CAMERA trial. Significant associations were observed for selected circulating miRNAs with biomarkers of cardiovascular risk in a population with coronary heart disease and insulin resistance. A significant association was found between the expression of miR103 with cardiac biomarkers, including troponin T and NT-pro-BNP, and miR122 with carotid intima media thickness. These associations supported previous observations that indicated an association between the upregulated miR122 expression and adverse lipid profile (Willeit et al., 2017a), and the role of lipid in the progression of carotid intima media thickness that was shown in a study by (Huang et al., 2016). In addition, upregulated miR103 expression in response to cardiac necrosis was observed in a study done by Wang et al. (2015a). Therefore, further research is needed to understand the specific role of miR103 in cardiac necrosis. The effect of metformin on the expression of circulating miRNA: The Carotid Atherosclerosis: MEtformin for insulin ResistAnce (CAMERA) trial : Metformin is the first line therapy for Type 2 diabetes. The effect of metformin on the risk of cardiovascular diseases had been studied in two randomised controlled trials: the UKPDS and the HOME trial. Those studies showed that metformin reduced the risk of CVD through surrogates in patients with diabetes. In this study, the effect of metformin on the expression of these circulating miRNAs was explored using both the baseline samples and the 18-month plasma samples from the CAMERA randomised control trial (RCT). Randomisation to metformin failed to show any effect on the expression of circulating miR30c, miR103, mi133a, miR122 and miR146a in a population without diabetes and with coronary heart disease, although the study was, perhaps, underpowered and the effect of metformin in the study in general was very modest. While no strong evidence for metformin having an effect on these miRNAs was observed, this was one of the first, if not the first, RCT to study miRNA biomarkers and provides a platform for future research in this area. Association of cardiovascular risk factors with carotid intima media thickness and pulse wave arterial stiffness in UK Biobank; Cross sectional study: More established vascular biomarkers of CVD were studied for the purposes of this thesis, in a much larger study than previously possible, in order to understand whether measurement of the markers might be clinically useful. In this first study, using the UK Biobank (42,727 participants), the determinants of vascular imaging biomarkers (carotid intima media thickness and pulse wave arterial stiffness index) were examined using traditional cardiovascular risk factors including systolic and diastolic blood pressure, HbA1c, lipid markers and anthropometric measurements. A cross-sectional analysis was done to investigate the upstream determinants for carotid intima media thickness and pulse wave arterial stiffness. Generally, systolic blood pressure and age were the strongest independent risk factors for a high cIMT value. It was found that, for every one SD increase in age and systolic blood pressure, the mean cIMT increased by 0.357 and 0.115 SD, respectively. Systolic blood pressure and age were the strongest independent risk factors for high PWASI. It was found that, for every one SD increase in age and systolic blood pressure, the mean PWASI increased by 0.005 and 0.046 SD, respectively. Also, this study showed that the cIMT was higher in males than females, along with other cardiovascular risk factors. This study, therefore, highlights potentially important differences in what these biomarkers indicate about upstream cardiovascular risk. Although both appear to be influenced by established risk factors, in line with the findings of much of the rest of the literature, they are different. This means they may have different clinical utility in different settings. Carotid intima media thickness and pulse wave arterial stiffness with association of cardiovascular events in UK Biobank: Prospective study: In this UK Biobank based study, the focus was on establishing whether carotid intima media thickness or pulse wave arterial stiffness index was associated with the incidence of cardiovascular diseases, stroke and CHD. In addition, we adjusted for the strongest established determinants based on findings of chapter 5 that include systolic blood pressure and age for cIMT, age and systolic blood pressure for PWASI. After adjustment, one SD increase of mean cIMT was associated with 50 % increase risk of incidence of CVD events. The incidence of CVD events increased in highest quantile (mean cIMT &gt;748µm) by 3 folds compared to persons in the lowest quantiles (mean cIMT &lt;588µm). While, per one SD change in PWASI, the risk of CVD events decreased by 13% after adjustment with age and gender over a median 3 years of follow up in United Kingdom. Therefore, it appears cIMT is the more convincing biomarker that reflects CVD risk in the short term. Overall conclusion: This study has demonstrated the potential utility of circulating miRNAs as novel biomarkers for cardiovascular disease, providing new data for the most promising miRNA biomarkers, in the context of a large and well standardised study relative to much of the rest of the literature. Also, the study reports on the upstream risk factors that are important potential determinants of imaging biomarkers as well as on the association between these imaging markers and incidence of cardiovascular disease in the large UK Biobank population. The understanding of these biomarkers might help in the future to develop the way cardiovascular disease risk is managed in the clinical setting.