Development of a minimally-invasive ultrasound guided rat myocardial infarction model to replace the gold standard invasive thoracotomy approach

In the UK, 7.6 million people are living with heart and circulatory diseases which are subsequently responsible for 27% of deaths, with myocardial Infarction (MI) and heart failure a major factor (BHF Factsheet 2024). Rodent MI models using infarcts generated via invasive thoracotomy have been the cornerstone of cardiovascular research, allowing investigation of the pathological mechanisms driving adverse outcomes, identifying imaging/therapeutic targets and evaluating novel therapies. Rats are particularly important to preclinical molecular imaging studies using positron emission tomography (PET), owing to their larger size vs. mice and the resolution of preclinical PET scanners (~1mm). In the last decade across the UK, 79 papers have been published using invasive rat MI models, representing the use of thousands of rats. This application aims to significantly reduce these numbers, and greatly refine these models which are classified as severe, through the development of a first-of-its-kind ultrasound guided minimally-invasive approach to MI generation in rats. This novel model, developed by embedding the 3Rs principals of reduction and refinement, will replace the gold standard approach of invasive infarct generation in rats and remove the need for: mechanical ventilation, skin incision, thoracotomy, lung collapse, pericardium rupture, exteriorisation of the heart, muscle/skin wound closure and breathing reflex recovery. Due to the exclusion of these aspects, we anticipate that our minimally-invasive model will result in a significantly higher recovery rate which will reduce the number of animals required, as well as reducing pain and suffering while shortening procedure and recovery times. Further to this, under ultrasound guidance, we propose that there will be greater control of infarct size, reducing the likelihood of unnecessarily large infarct sizes and missed occlusions. These expectations are based on an equivalent minimally-invasive model in mice using permanent occlusion to generate MI which has recently been developed and is now in use in our research centre(1,2). This published mouse model provides the blueprint for our first-of-its-kind rat model and establishes the proof-of-concept that this can be achieved in rodents, increasing our likelihood of success. The aims of this project are to 1)develop a rat ultrasound phantom to be used for equipment optimisation and future training purposes, 2)establish the recovery, accuracy and actual severity of this proposed minimally-invasive rat approach using permanent coronary artery occlusion and 3)for the first time in any rodent species establish a minimally-invasive method of temporary coronary artery occlusion to induce reperfusion injury-driven MI in rats.