Approach

We have built a consortium, CRUCIAL, which will develop a coordinated program to investigate the role of microvascular rarefaction in cognitive impairment and heart failure. Diagnosis of microvascular rarefaction is limited by the inability to assess microvascular density. We will develop advanced imaging tools taking advantage of the newest MRI technology including non-contrast and artificial intelligence methods to assess brain and heart microvascular rarefaction. We will also develop other non-invasive measures that will be cheaper and easier to widely disseminate in clinical practice (sublingual and retinal microvascular imaging, and blood microvesicle analysis). We will then apply these techniques to prospective cohorts with cognitive impairment and heart failure to demonstrate that rarefaction can be used as a biomarker to diagnose and stratify patients. Microvascular regression is now recognised as an active process. We will therefore investigate the molecular mechanism of vessel rarefaction in the presence of comorbidities that could be targeted therapeutically. Therapeutic options for cognitive impairment or heart failure are currently limited to treating co-morbidities. The aim of CRUCUAL is to deliver diagnostic tools to clinician and therapeutic pathways to pharma that target microvascular health in order to prevent cognitive and cardiac disease progression, reduce morbidity and ultimately improve quality of life for patients.

The overall concept of the application is that vascular rarefaction is a common mechanism between cardiac and neurological diseases that arise from metabolic comorbidities. Both these diseases have no treatment options. We propose that by identifying patients showing vascular rarefaction, we can identify those that are at risk of developing heart failure and/or vascular dementia. We propose that by studying the mechanism of rarefaction, we can identify pharmacological targets that could prevent vessel rarefaction and therefore inhibit disease progression. 

This project aims to develop microvascular perfusion measurements by MRI as a method to identify microvascular rarefaction. We will do this both by advanced imaging techniques but also by validating that the changes in microvascular/myocardial perfusion correlate to changes in microvascular density. The advancement of the imaging technology will be done through a collaboration between industry and clinical scientists. This will establish microvascular perfusion as a key biomarker to stratify patients with cognitive impairment and/or heart failure.

We also aim to show that measuring microvascular density and/or perfusion is an important clinical parameter. This could ultimately lead to a change in the diagnosis criteria in VCI and/or HF. We will study whether rarefaction is a causative mechanism of disease progression in VCI (mental disease) and HFpEF (non-mental disease). The heart and brain share a special link because the functional cell unit of both organs are long-lived cells that are post-mitotic and are interlinked with their vascular supply; they share the need for high levels of oxygen for adequate organ function making them more sensitive to ischaemia. By studying this, both in patients and in animal models, we can investigate how microvascular rarefaction relates both to onset and to progression of VCI and HFpEF.

We will investigate other possible biomarkers of vessel rarefaction. MRI is expensive and since rarefaction is likely not limited to the heart and brain, we will investigate whether we can identify rarefaction more cost-effectively (e.g. whether regressing vessels release microvesicles that could be used as a biomarker, or sublingual/retinal microvascular changes). This will represent a significant cost reduction for identification of vessel rarefaction.

We will investigate sex difference in all patient cohorts and in the experimental model. Women with comorbidities have a higher risk of developing HFpEF and VCI than men with the same comorbidities. Insight from sex differences could therefore identify causal mechanisms.

We also have preliminary results identifying the anti-oxidant pathways being dysregulated in the presence of comorbidities. The objective is that by studying oxidative stress handling in the presence of comorbidities, we could identify target gene pathways to develop drugs against vessel rarefaction in VCI and HF.