3D heart models to understand genetic and pathway-related factors that drive electromechanical physiology in humans

This project aims to understand genetic and pathway-related factors driving electromechanical physiology in humans using 3D computer models. 3D models and simulations provide an alternative to the often slower and more expensive in vivo and in vitro methods. Further potential of 3D cardiological models includes their transferability, adaptability as well as accurate replication of simulated processes and their parameters. Different scales, such as cellular, tissue and whole heart level, can be represented in the same model resulting in a comprehensive and detailed perception.
Further research into 3D cardiovascular models will aid to grow their potential to be applied as a foundation for future therapies. Understanding the implications of genetic variability on the functioning of the heart and being able to simulate those accurately will allow for further studies on patient-specific adaptation of models and therapies. As stated by Corral-Acero et al. (2020), "Providing therapies tailored to each patient is the vision of precision medicine".
The underlying research question of this project is how perturbing molecular and genetic variations affect the functioning of the heart. As part of this, correlation and effects of drug therapies and therapeutic intervention will be considered. To simulate variabilities and identify responsible causes, this project will make use of computational modelling, including models such as the ToR-ORd (Tomek, et al., 2019), well-established simulation software, such as CHASTE, and high-performance computing. It aims to build on and complement previous studies on the variability of ion channels affecting the electrophysiological and mechanical activity of the heart. As a novelty point of focus it will investigate variations in pathways involved in contractile functioning and calcium handling. As a result, this research plans to present the impact of variabilities of those pathways, which may be induced by therapeutic intervention, on the overall electromechanical functioning of the heart.
A key objective of this research will be to simulate state-of-the-art biological knowledge on electromechanical processes within and variability of single cells on a subcellular level. Using this model, different cell-types will be compared. The model will then be expanded to capture functioning of the heart at organ level representing physiological features and precise geometrical representation. A final objective will be to use the developed model to simulate effects of genetic and molecular variability under different conditions such as varying heart rate and pharmacological influences. To evaluate results and the workings of the simulation, experimental data, such as clinical data, human stem cell-derived cardiomyocyte data and data concluded from in vivo animal models, will be consulted. The collaboration with the industry partner will give unique opportunities in accessing such data.
This project falls within the BBSRC research area of tools and technology underpinning biological research.
This research will be conducted under the supervision of Professor Blanca Rodriguez within the group of Computational Cardiovascular Science at the University of Oxford. It will be carried out in collaboration with AstraZeneca as a partner in industry.

References
Corral-Acero, J. et al. (2020), The 'Digital Twin' to enable the vision of precision cardiology. European Heart Journal, [online] ehaa159, p. 1-11, Available at: https://doi.org/10.1093/eurheartj/ehaa159 [Accessed 09 Oct. 2020].
Tomek, J. et al. (2019), Development, calibration, and validation of a novel human ventricular myocyte model in health, disease, and drug block. eLife, [online], 8:e48890, doi: 10.7554/eLife.48890, Available at: https://elifesciences.org/articles/48890 [Accessed 09 Oct. 2020].