Manganese-enhanced magnetic resonance imaging of the myocardium
Item statusRestricted Access
Embargo end date31/07/2022
Spath, Nicholas Burton
Background Current clinical cardiac magnetic resonance imaging uses gadolinium contrast to detect myocardial pathology by characterising the extracellular space. Whilst a valuable clinical tool, gadolinium-based media cannot describe intracellular myocardial function due to their extracellular distribution. Manganese, a biologically active paramagnetic calcium analogue avidly taken up into cardiomyocytes via voltage-gated calcium channels, has potential to track and quantify intracellular calcium transport. The aims of this thesis are to investigate the feasibility and utility of manganese-enhanced magnetic resonance imaging (MEMRI) of the myocardium in differing aetiologies of myocardial dysfunction. Methods and Results First, I assessed MEMRI in a preclinical model of myocardial infarction and developing ischaemic cardiomyopathy over time. I demonstrated that MEMRI quantified myocardial infarction more accurately than delayed gadolinium enhancement, in comparison to the gold-standard of histopathology. Furthermore, greater manganese uptake was detected in remote myocardium in established ischaemic cardiomyopathy than in the acute phase, indicating potential to detect altered calcium-handling in remodelling myocardium. I then undertook direct comparison of MEMRI with the mechanistically comparable gold-standard measure of myocardial viability, 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET). Manganese-enhanced MRI demonstrated strong agreement with both 18F-FDG PET and histopathological quantification of viability in a preclinical model. No clinical study of MEMRI in patients with cardiomyopathy has been undertaken to date. I undertook clinical study of MEMRI in patients with reperfused ST-elevation myocardial infarction, during the immediate acute phase and following recovery. Using kinetic modelling, I described the dynamic uptake of manganese in acute and established myocardial infarction as well as remodelling myocardium, in comparison to healthy control subjects. Importantly, I showed that MEMRI differentiated infarcted, stunned and viable myocardium, and correlated with myocardial dysfunction better than delayed gadolinium enhancement. Finally, I applied MEMRI to non-ischaemic cardiomyopathy in patient cohorts with either dilated or hypertrophic cardiomyopathy. Using kinetic modelling, myocardial manganese uptake demonstrated stepwise reductions across healthy myocardium, hypertrophic cardiomyopathy without fibrosis, dilated cardiomyopathy and hypertrophic cardiomyopathy with fibrosis. I showed that MEMRI discriminated absolutely between the healthy and fibrosed myocardium, providing a non-invasive measure of altered myocardial calcium-handling in non-ischaemic cardiomyopathy. Conclusion I have demonstrated utility and feasibility of myocardial MEMRI in preclinical models of myocardial fibrosis, confirming these findings in early clinical translational studies. In ischaemic heart disease, MEMRI can define manganese uptake in infarcted, stunned and viable myocardium, with potential to identify viability more directly and more accurately than current techniques allow. In non-ischaemic cardiomyopathy, I have described how MEMRI can detect myocardial dysfunction as a reflection of altered calcium-handling and accurately discriminate health and disease. Overall, I have demonstrated that MEMRI can be applied to a wide range of myocardial disease processes, with potential to enhance early disease detection, to monitor disease progression, to assess response to therapy and to improve prognostication.