Feasibility of replacing invasive heart pressure measurements with non-invasive MR Elastography to reduce rodent numbers in pre-clinical research
Lead Research Organisation:
University of Oxford
Department Name: RDM Cardiovascular Medicine
Abstract
Magnetic resonance imaging (MRI) is a technique used to investigate size, structure and function of the heart. However, conventional MRI does not provide information on the pressure that the heart muscle must generate in order to pump blood through the body. This pressure is a fundamental parameter of cardiac function and can currently only be determined by inserting a catheter directly into the heart. Particularly in mice and rats, which are the predominant animal species used in cardiovascular research, this is an invasive and technically very challenging procedure that can be performed only once. We therefore propose to investigate whether or not a novel MR technique can overcome this limitation, and can be used to measure the pressure in the heart of mice and rats without inserting a catheter into the animal. If successful, this method will represent a valuable tool for scientists studying progression and treatment of heart disease, but most importantly it will reduce the numbers of animals required for this type of research by obviating the need to kill animals simply to obtain basic cardiac pressure measurements.
Technical Summary
Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) are sophisticated phenotyping techniques that allow for a non-invasive characterization of cardiac function, anatomy, structure and metabolism in rodents. However, when assessing myocardial function the isovolumic phases of the cardiac cycle are not directly accessible to imaging techniques, yet this is where maximal rates of pressure generation and relaxation occur. This type of information is only available using LV catheterization, which in rodents is an invasive and terminal procedure, requiring new experimental groups for every time-point. Magnetic Resonance Elastography (MRE), which measures shear deformation following mechanical tissue stimulation, has the potential to non-invasively assess ventricular pressure in vivo, as successfully demonstrated in pig and in human hearts. However, this technique has not yet been applied to rodent hearts. We hypothesize that MRE can also be used to non-invasively measure left-ventricular pressure-volume curves with sufficient temporal resolution to detect subtle phenotypes in surgically and genetically manipulated rodents. We therefore propose to conduct a pilot study with the aim to develop the tools, which will be necessary to investigate this hypothesis. If successful, MRE will have the potential to replace the invasive and terminal hemodynamic procedure in basic cardiovascular research, leading to a reduction in animal usage.
Planned Impact
Several areas/groups of beneficiaries of the proposed project can be identified:
Firstly, the project will facilitate and benefit pre-clinical research. Given the multi-disciplinary nature of the project, the three PIs represent a considerable number of sections of this group, including basic cardiac research, animal physiology, cardiovascular medicine, and magnetic resonance imaging. Furthermore, the PIs have strong collaborations at national and international levels. Specifically, Oxford has a leading role within the consortium of four research sites (i.e. Edinburgh, Kings College and University College, London, and Oxford, respectively), funded in the BHF's major strategic investment into basic cardiac imaging research about nine years ago. The four sites share the same MR system platform and focus on cardiac MR research (i.e. development and application). The outcome of this proposal is of direct relevance for the research within this consortium.
Secondly, in the longer run, the project will serve the medical community by developing novel tools that will, for the first time, allow for a longitudinal assessment of a fundamental cardiological parameter, which has so far been beyond the scope of any non-invasive imaging modality. By providing a new and more sensitive phenotyping method, this technique will help to establish platforms that can for example be used to develop and test novel therapies for heart disease.
Thirdly, the project fundamentally embraces the concept of the 3Rs (Reduction, Refinement, and Replacement of animal-based research). Advancing MR techniques to be applicable, non-invasively, to high-fidelity function studies enables a reduction in the number of animals required for research. This will eventually find reflection in study designs, where each heart serves as its own control, and where disease development can be studied longitudinally. Stringent intra-individual control and validation provides for more powerful statistical analyses in an otherwise highly inhomogeneous biological model, and thus, reducing the number of animals needed for basic cardiovascular research. More specifically, about 100 haemodynamic measurements on rodents are conducted in our laboratory annually, which could all be replaced by the proposed technique. Furthermore, literature search over the past four years yielded an estimate of several thousand mice and rats in the UK / worldwide for this kind of measurement alone, and we suggest that these numbers could also be significantly reduced.
Last but not least, considering the burden heart disease places on the individual and their families, the economy, and the social and health systems in the developed world, the technique provided by this proposal will be of general societal benefit, as the outcome of this work will fundamentally contribute to the understanding of normal and patho-physiological processes of the heart.
Firstly, the project will facilitate and benefit pre-clinical research. Given the multi-disciplinary nature of the project, the three PIs represent a considerable number of sections of this group, including basic cardiac research, animal physiology, cardiovascular medicine, and magnetic resonance imaging. Furthermore, the PIs have strong collaborations at national and international levels. Specifically, Oxford has a leading role within the consortium of four research sites (i.e. Edinburgh, Kings College and University College, London, and Oxford, respectively), funded in the BHF's major strategic investment into basic cardiac imaging research about nine years ago. The four sites share the same MR system platform and focus on cardiac MR research (i.e. development and application). The outcome of this proposal is of direct relevance for the research within this consortium.
Secondly, in the longer run, the project will serve the medical community by developing novel tools that will, for the first time, allow for a longitudinal assessment of a fundamental cardiological parameter, which has so far been beyond the scope of any non-invasive imaging modality. By providing a new and more sensitive phenotyping method, this technique will help to establish platforms that can for example be used to develop and test novel therapies for heart disease.
Thirdly, the project fundamentally embraces the concept of the 3Rs (Reduction, Refinement, and Replacement of animal-based research). Advancing MR techniques to be applicable, non-invasively, to high-fidelity function studies enables a reduction in the number of animals required for research. This will eventually find reflection in study designs, where each heart serves as its own control, and where disease development can be studied longitudinally. Stringent intra-individual control and validation provides for more powerful statistical analyses in an otherwise highly inhomogeneous biological model, and thus, reducing the number of animals needed for basic cardiovascular research. More specifically, about 100 haemodynamic measurements on rodents are conducted in our laboratory annually, which could all be replaced by the proposed technique. Furthermore, literature search over the past four years yielded an estimate of several thousand mice and rats in the UK / worldwide for this kind of measurement alone, and we suggest that these numbers could also be significantly reduced.
Last but not least, considering the burden heart disease places on the individual and their families, the economy, and the social and health systems in the developed world, the technique provided by this proposal will be of general societal benefit, as the outcome of this work will fundamentally contribute to the understanding of normal and patho-physiological processes of the heart.