Content

Research Themes

The ICER Forum supports a number of research activities. A number of key research themes are listed below, with background information and summary of ongoing work. If you have expertise you want to share, or if you are interested in collaborating in these research projects, please don't hesitate to contact us.

 

MODELLING THE PATHWAYS TO ENDOTHELIAL DYSFUNCTION

SUB-THEMES:

  1. LOCAL REGULATION OF BLOOD FLOW
  2. VASCULAR SIGNALLING, INCLUDING SECOND MESSENGER PATHWAYS INVOLVED IN VASCULAR TONE AND REACTIVITY
  3. THE ROLE OF NITRIC OXIDE, PURINES AND PYRIMIDINES; FLOW-INDUCED ATP RELEASE AND CONDUCTED RESPONSES
  4. THE ROLE OF GEOMETRY, LOCAL HAEMODYNAMICS, WALL SHEAR STRESS AND MASS TRANSPORT IN ATHEROGENESIS
  5. INTEGRATED AND MULTI-SCALE MODELS OF THE CARDIOVASCULAR SYSTEM

KEYWORDS: patient-specific, image-based modelling, computational models, wall shear stress (WSS), mechanotransduction, receptor-mediated pathways, mass transport, endothelium.

BACKGROUND: The endothelium consists of a monolayer of cells lining the inner surface of blood vessels. Although we cannot characterise in full details how endothelial cells in vivo respond to haemodynamic stimuli, and how these responses are influenced by mass transport phenomena, we know that they play an important role in modulating vascular tone and reactivity. Major cardiovascular adverse events are associated, at an early stage, with symptoms of impaired vascular reactivity and dilator function. In particular, numerous studies have shown the existence of a positive correlation between abnormal mass transfer, low and oscillatory wall shear stress resulting from specific geometrical features and/or disease state and the development of atherosclerotic plaque.

SUMMARY OF ONGOING WORK: Anatomically accurate geometric models of the blood vessel lumen are essential for realistic flow simulations. Our group has developed a robust and semi-automatic modelling pipeline for blood flow through subject-specific arterial geometries, consisting of image segmentation, domain discretisation and fluid dynamics. Models of ATP transport, hydrolysis and release have been used in a number of cases, mostly based on experimental settings (parallel plate flow apparatus, 2D channels, etc.). Recently, results were presented to compare two existing models of WSS-dependent ATP release by the endothelium in a patient-specific carotid geometry. Simulations revealed the inadequacy of such models for more physiologically realistic settings. Our group is currently trying to develop a general framework for modelling the different mechanisms associated with endothelium-mediated vasodilation (ATP release by the endothelium, oxygen-dependent release by erythrocytes, ATP-induced ATP release and generation/degradation by soluble nucleotidases, intracellular calcium (Ca2+) dynamics involved in the production of nitric oxide, nitric oxide production/consumption and diffusion, endothelium-derived relaxation factors, etc.). The resulting models can be used jointly with rheological models and/or fluid-structure interaction problems.

The long-term goal is to be able to ascertain how and under what conditions the endothelium “switches” from a normal state to a dysfunctional state. In addition to the traditional cardiovascular risk factors, some local deterministic factors might also need to be considered in a novel approach to screening individuals (risk assessment for cardiovascular disease).

POTENTIAL FOR COLLABORATIVE WORK:

  • One of the main difficulty we face is that all the knowledge available is based on experimental data which almost never reflect the truephysiological environment. Advances will rely on a combination of computational models, innovative experiments (bioreactors capable of replicating physiological transport and WSS) and in vivo data (ATP plasma concentration at different locations in the human body, under different physiological conditions, flow-mediated dilation experiments, etc.)

  • Cardiovascular scientists and clinician's views are essential in the success of this project. Smaller collaborative projects can be devised on sub-themes, using either or both medical images, clinical experiments/validation and or results from longer term clinical studies. Consultation can also be arranged on a case by case basis (clinicians needing engineering expertise in patient-specific cardiac device modelling, patient-specific blood flow studies for a given medical condition, etc.)