Manganese-based MRI: A sensitive and safe way to directly visualize heart cell viability

By Adrienne Mueller, PhD

Heart muscle cells are one of the few cell types in the body that do not regenerate. When they die, they cannot be replaced. Coronary artery disease and heart attacks reduce blood flow to your heart, eventually causing tissue death. This condition is called ischemic cardiomyopathy and is the leading cause of death worldwide. In order to help treat or remove damaged heart tissue, the first thing you need to do - is find it.

The status quo – No direct measure of heart cell viability

Clinicians and researchers visualize heart tissue using magnetic resonance imaging (MRI). In cardiac MRIs, contrast agents are used to distinguish between healthy and damaged heart tissue. Traditional contrast agents, such as gadolinium, indicate what parts of the heart are damaged by accumulating in poorly perfused tissue. But, gadolinium also has a limitation: it accumulates outside of the heart cells and is not taken up by the cells directly. Researchers have therefore long-desired a more direct agent to measure heart cell viability: one that actually labels and distinguishes the healthy and injured cells.  

Enter Manganese

Manganese is a fantastic new candidate contrast agent for cardiac MRIs, because it is similar in size and shape to calcium and is therefore able to enter only the live and injured heart cells. Moreover, because calcium is the main driver of heart electrical activity and contractions, the cell’s uptake of manganese also provides a direct readout of heart health. Healthy cells would take up manganese exactly as they would calcium, whereas damaged cells would take up less, and dead cells none. Therefore, in an MRI, heart tissue loaded with manganese is viable, and that without – is not. Unfortunately, manganese’s similarity to calcium, also means it runs the risk of being cardiotoxic by displacing calcium in the heart cells and reducing their ability to function. Recently researchers have created a modified version of manganese that is less cardiotoxic, but still maintains the desirable calcium-like qualities. The big question is – how well does it work?

Both gadolinium and manganese contrast agents detect heart tissue damage. Gadolinium detects fibrosis in myocardial infarction and manganese detects nonviable myocardium.

Clinical Trial - Will it work and is it safe?

Having previously demonstrated the utility of manganese-based contrast agents in pigs, the lab of Phillip Yang, MD received FDA approval to establish the safety and feasibility of manganese-based contrast agents in humans. They embarked on a pilot study, recently published in the Journal of American College of Cardiology: Cardiovascular Imaging, to compare manganese- and gadolinium-based contrast agents’ ability to detect damaged heart tissue in patients with ischemic cardiomyopathy.

As Yuko Tada, MD, PhD et al report, the investigators imaged the hearts of 24 ischemic cardiomyopathy patients using both methods and compared the results. First, they found that the new manganese-based contrast agent worked – the investigators were able to distinguish damaged and healthy heart tissue in human patients. Second, they also showed that use of this new agent had no severe adverse side effects. When they compared the readouts between the two methods, they found that the manganese-based method revealed a smaller portion of heart was damaged than the gadolinium-based method showed – indicating the manganese-based MRI is a more precise tool for determining heart cell viability. However, it was still easier to discriminate damaged tissue from healthy tissue using the gadolinium-based method.

Tada et al show that manganese-based MRI can be successfully used in humans with no adverse side-effects. The authors further suggest that, for now, a combined approach of gadolinium and manganese-based contrast agents will provide the most clear and sensitive information about a patient’s damaged heart. This study has opened the door to the use of a new tool to directly measure heart muscle viability in humans, and future research with this method will doubtless provide valuable, clinically-relevant information for treating ischemic cardiomyopathy.

Other Stanford Cardiovascular Institute-affiliated authors who contributed to this study include Michelle Santoso, Shahriar Heidary, Hiromi Sano, Atsushi Tachibana, and Yuka Matsuura.

Dr. Yuko Tada

Dr. Phillip Yang