Characterisation of post ischaemic cardiac remodelling in rodent and porcine models of cardiac injury

Introduction: Cardiovascular diseases remain a major cause of morbidity and mortality worldwide. There is a large number of patients who suffer from myocardial infarction (MI). However, the a hearts of majority of patients who survive an MI will undergo substantial changes that will lead to heart failure (HF). The aim of this work is to characterise post ischaemic cardiac remodelling in two different experimental models using rats and pigs. A clinical study was also planned to identify acute changes in the blood metabolome of patients undergoing primary percutaneous coronary intervention (PPCI) following ST elevation myocardial infarction (STEMI) and correlate with long term recovery. The obtained information will help in identifying targets for therapeutic interventions, which can reduce the likelihood of adverse cardiac remodelling, and therefore heart failure. Methods: Adult rats undergoing left anterior descending (LAD) coronary artery ligation and pigs with LAD coronary artery balloon occlusion were used in this work. SHAM operated rats and healthy pigs were used as control. After initiation of cardiac injury, the animals were monitored for 4 weeks before termination. Cardiac injury and function 4 weeks after interventions were assessed using echocardiography and cardiac proteins release in pigs. Hearts and blood samples were extracted and collected. Nuclear magnetic resonance spectroscopy was used to assess metabolic profile of blood and cardiac tissues. Cardiac energy metabolites were measured using high performance liquid chromatography. Cardiac protein and phospho-protein quantification were carried out using liquid chromatography tandem mass spectrometry. Histological analyses of infarcted and control hearts were conducted using light and electron microscopies to detect ultrastructural differences. Ethical application and protocol for the clinical study were granted. Results: Post ischaemic cardiac remodelling in rodent and porcine hearts was associated with increased cardiac fibrosis and wall thickening of small to medium size arterioles. Ultrastructural analysis showed characteristics of ongoing structural remodelling in the extracellular matrix and the presence of fibroblasts and telocytes. There was disruption to mitochondrial cristae density and distribution. No significant changes were detected in cardiac energetics in infarcted and control tissues of rats and pigs. Proteomics and phosphoproteomics analyses revealed evidence of sustained oxidative stress and inflammation, in addition decrease of mitochondrial respiration and metabolism proteins, modification to calcium cycling, z disc and selected extracellular matrix proteins and collagen subtypes. There was increase in certain metabolites with post ischaemic remodelling, mainly ketone bodies in rodents and porcine blood, and taurine in porcine cardiac tissues. The clinical study was suspended due to Covid-19 pandemic. Conclusion: Post ischaemic cardiac remodelling is associated with substantial cellular, molecular and metabolic changes in rodent and porcine models of cardiac injury. Importantly, the increase in blood ketone bodies in both models, in addition to decreased porcine blood taurine level could potentially be investigated furthermore in patients to target adverse cardiac remodelling and design therapeutic intervention for heart failure.