Clinical Translation: Manganese-Enhanced MRI of the Myocardium

Manganese holds great promise for cardiac MRI. As a calcium analogue, manganese-enhanced MRI provides direct imaging of viable calcium handling, with potential to define myocardial viability more accurately than with current gold-standard methods, as well as detect calcium-handling dysfunction in failing cardiomyocytes.

Combination of 4 MRI images

Research Methods and Objectives

Manganese-enhanced MRI (MEMRI) offers an alternative form of cardiac imaging to current methods, with potential to provide more accurate information about the functionality of the myocardium and in the future could help to diagnose and guide therapy in patients with heart failure.

Manganese, a calcium analogue, enables novel manganese-enhanced MRI (MEMRI) which has the potential to identify viable myocardium and quantify calcium influx and handling. Two distinct manganese contrast media have been developed for clinical application, employing different strategies to mitigate against adverse effects resulting from calcium-channel agonism. Using myocardial T1 mapping, we aimed to explore these manganese contrast agents, their mechanism of myocardial uptake, and their application to infarcted hearts. Furthermore, we undertook a further validation step comparing MEMRI with 18F-FDG  PET to assess intramyocardial viability with a view to clinical translation.

In a series of preclinical studies, we have performed T1 mapping in healthy adult male rats using manganese-based contrast media, with and without co-administration of calcium-channel blockade. A second cohort of rats underwent surgery to induce anterior myocardial infarction by permanent coronary artery ligation, or sham surgery. Rats were imaged with current gold-standard gadolinium delayed-enhancement MRI (DEMRI) in addition to MEMRI to allow comparison. A further cohort of infarcted animals underwent imaging with 18F-FDG PET and MEMRI as a validation step.

Our work to date has shown that both manganese agents induce concentration-dependent shortening of myocardial T1 values.  This was greatest with the non-chelated manganese agent, and could be inhibited by 30-43% with calcium-channel blockade. MEMRI successfully delineated the area of myocardial infarction with good agreement with histology. In contrast, DEMRI methods overestimated infarct size. In addition, increased manganese uptake was observed in the remote myocardium, with remote myocardial ∆T1 inversely correlating with left ventricular ejection fraction post myocardial infarction. In the validation step, MEMRI showed excellent agreement with 18F-FDG PET definition of viability.

MEMRI causes concentration and calcium channel-dependent myocardial T1 shortening. MEMRI with T1 mapping provides an accurate assessment of infarct size and can also identify changes in calcium handling in the remote myocardium. This technique has potential applications for the assessment of myocardial viability, remodelling and regeneration. Our clinical study, commencing May 2018, investigating MEMRI in patients with ischaemic, dilated and hypertrophic cardiomyopathy as well as healthy volunteers will investigate this further.

Principal Investigator, Co-Investigators, Other researchers

David Newby (CI), Nick Spath (PI), Gillian GrayMarc Dweck, Scott Semple, Maurits Jansen