bioMarkers linking Obstetric events to Major cardiovascular outcomes (MOM)
Dr. Louise Pilote, McGill University
Duncan Stewart, Ottawa Hospital Research Institute
Natalie Dayan, McGill University Health Centre
Stella Daskalopoulou, McGill University Health Centre
Kenny Schlosser, Ottawa Hospital Research Institute
Rhian Touyz, University of Glasgow
Christian Delles, University of Glasgow
The proposed research program aims to identify sex-specific risk factors that may contribute to differential health outcomes experienced by women with heart disease. Of particular interest is the link between hypertensive disorders of pregnancy (HDP) and increased risk for future cardiovascular disease (CVD). Specifically, the proposed research program will allow us to examine the biological pathway in which endothelial dysfunction (ED) and systemic inflammation occurring during hypertensive pregnancy may accelerate vascular aging, potentially predisposing women to CVD.
Prognostic biomarkers, such as microRNA (miRNA) and proteins, may be implicated in sustained vascular ED post HDP. Within our GENESIS-PRAXY cohort of women with acute coronary syndrome (ACS), preliminary data demonstrated differential miRNA expression patterns among those with HDP relative to those with normotensive pregnancy. In addition to miRNA, specific protein biomarkers involved in angiogenesis have also been studied in the relationship between HDP and ED, including placental growth factor (PIGF), soluble fms-like tyrosine kinase (sFlt-1), and soluble Endoglin (sEng). Given their clear role in HDP pathogenesis, both miRNA and protein biomarkers offer potential as practical non-invasive markers of premature vascular aging in sustained ED. In summary, our miRNA and protein biomarker data require validation in larger cohorts of women, with and without ACS, in order to better ascertain the prognostic role of these novel biomarkers.
The proposed research program demonstrates relevant contribution to the Networks Theme 2, measurement improvement and treatment of vascular disease, through its identification of novel biomarker measurement methods and its utility in early detection of vascular conditions. The proposed research program also shows relevance to the sub-committee “leveraging large cohort to identify factors associated with microvascular dysfunction.” Our project is interconnected with other CVN projects that examine the role of biomarkers in the pathology of vascular cognitive impairment and their utility as a measurement tool. Specifically, our project objectives are defined within the infrastructure of CVN through the use of basic science to inform prevention and treatment of vascular conditions.
Harmonized assessment of common disease mechanisms and biomarkers in rodent models of vascular cognitive impairment and heart failure
Dr. Mansoor Husain, Toronto General Research Institute
Baptiste Lacoste, University of Ottawa
Dale Corbett, University of Ottawa
Kim Connelly, St. Michael’s Hospital
Makon-Sébastien Njock, University of Liège
Brian Amsden, Queen’s University
Frédéric Lesage, École Polytechnique Montréal
Terence Ozolins, Queen’s University
Carmela Tartaglia, Toronto Western Hospital
Howard Chertkow, McGill University
Epidemiological studies suggest a link between cardiovascular (CV) risk factors, especially type-2 diabetes (T2D), and vascular cognitive impairment (VCI), vascular dementia (VaD) and Alzheimer’s disease (AD). Chronic hyperglycemia induces cerebrovascular inflammation and oxidative damage, which contribute to cognitive impairment and dementia. Early detection of inflammatory processes in brain could provide prognostic information about disease course, would improve clinical management, and facilitate evaluating the effectiveness of therapies in patients at risk for VCI and dementia. However, to date, non-invasive biomarkers are not available. With this Team project we aim to validate circulating extracellular vesicles (EVs) and their microRNA (miR) contents as non-invasive biomarkers of cerebrovascular inflammation and VCI progression that could be easily detected in a blood test. This innovative proposal emerges from recent exciting findings from our labs: Fish and Husain have demonstrated that circulating EVs play an anti-inflammatory role in healthy mice, mediated in part by the transfer of anti-inflammatory miRs to recipient cells (e.g. endothelial cells and monocytes). They have developed a robust assay to assess whether the anti-inflammatory function of EVs/miRs is compromised in mouse models of VCI and, importantly, they have confirmed the loss of EV/miR anti-inflammatory properties in a mouse model of T2D (Leptin receptor deficiency, db/db). The Hamel lab has confirmed that exacerbated white matter (WM) inflammation accompanies cognitive deficits in a cohort of transforming growth factor-β1 (TGF-β1) transgenic mice treated with low doses of steptozotocin-nicotinamide to induce mild T2D. TGF mice display cerebrovascular pathologies similar to those found in VaD and AD but no overt signs of cognitive failure unless they are combined with mild T2D. These results suggest that a compromised cerebrovasculature facilitates an exacerbated WM inflammation induced by slightly increased glucose levels that presumably leads to cognitive impairments. This is a promising model for testing the utility of using EVs and miR as biomarkers of VCI. The Bennett lab has developed a new model of oxidative stress- induced cognitive impairment, based on deletion of aldehyde dehydrogenase-2 (Aldh2), which induces age- related vascular and AD-like pathologies. By studying EVs/miRs in a mouse model of VCI unrelated to hyperglycemia effects in the brain, we will be able to determine the robustness and diagnostic/prognostic value of using EVs/miRs as generic biomarkers of VCI.
We will compare several disease parameters (WM inflammation and lesions, blood-brain barrier (BBB) disruption, tau phosphorylation, Aβ pathology, cognitive performance) in three different mouse models of VCI to better understand disease course. We will then identify and evaluate circulating biomarkers (EV size, abundance, function and miR content) in these models to identify commonalities. Finally, we will assess whether these models also have defects in cardiac contraction/relaxation, since there are strong links between cardiac dysfunction and cognitive deficits in humans. Future directions will measure these biomarkers in human populations with VCI.