Manganese Enhanced Magnetic Resonance Imaging (MRI) in Ischaemic and Takotsubo Cardiomyopathy.

Scanning the heart using magnetic resonance imaging (MRI) enables detailed assessment of its structure and function. MRI can give more detailed information about the heart by using a contrast 'dye' that is injected into a vein during the scan. This can highlight abnormal areas within the heart. Current contrast dyes help identify scarring within the heart. Recent studies using a new contrast dye containing manganese has been used in patients with diseased heart arteries (ischemic heart disease) and cardiac conditions affecting the heart muscle (cardiomyopathy). This has shown abnormal uptake of the dye in patients with ischemic heart disease and various cardiomyopathies. It has also shown advantages over traditional contrast; firstly, it can measure the amount of scar more accurately and secondly it can quantify scar.

Heart failure is a condition in which the heart muscle is weakened and pumping function is reduced. It is caused by various conditions including different heart muscle diseases and those affecting the heart arteries. Heart failure is a global pandemic affecting at least 26 million people worldwide. Despite the significant advances in therapies and prevention, mortality and morbidity are still high and quality of life poor. Heart failure imposes both direct and indirect costs to healthcare systems and has a significant impact on global health.

We plan to further test this manganese containing dye as we believe it will provide better understanding into reversible cardiac conditions. Our study will be conducted in the Queen's Medical Research Institute (QMRI) at the Royal Infirmary Edinburgh led by Dr Trisha Singh. This is a clinical study which will involve using this new contrast agent to scan three patient groups; i) heart attacks by a blocked heart artery (ii) heart disease caused mismatch in blood supply and demand (angina) (iii) heart disease secondary to a stress response (takotsubo). We will scan healthy volunteers for comparison.

We believe this new agent has potential to better measure disease in the heart, improve our ability to establish the cause of heart disease and help monitor the disease over time as well as guide future treatment for individual patients. This has the potential to change clinical practice and make an impact on patient care.

Cardiac magnetic resonance imaging is used to assess myocardial structure, function and tissue composition. This can be further enhanced using contrast media that target certain biological functions. As an analogue of calcium, manganese is readily taken up into viable cardiomyocytes where it increases T1 relaxivity. In previous work at the Centre for Cardiovascular Science at the University of Edinburgh, we have conducted proof-of-concept studies demonstrating that manganese-enhanced magnetic resonance imaging can delineate myocardial infarction better than gadolinium and is associated with alterations in myocardial T1 values in patients with dilated cardiomyopathy. We here propose to extend our findings to patients with either ischaemic myocardium or takotsubo cardiomyopathy, and to explore the recovery of transiently dysfunctional myocardium. We hypothesise that manganese-enhanced T1 mapping will identify substantial alterations in calcium handling during the early phases of ischaemic and non-ischaemic left ventricular systolic impairment, and that these will reverse following recovery of the myocardium. This has major potential to assist in the understanding, diagnosis and potential treatment of these conditions and establish a role for manganese-enhanced T1 mapping for myocardial viability. We believe that this will form an outstanding project for Dr Singh's Clinical Research Training Fellowship.

Impact will be generated through the following benefits:

-Improved knowledge base within cardiovascular research: Though manganese has been used as a contrast agent in the past, it has not been fully explored in cardiac imaging with T1 mapping. The principal potential advantage of T1 mapping compared to late gadolinium enhancement relates to its ability to detect diffuse more subtle forms of myocardial disease and to provide quantification rather than a binary "black versus white" categorisation. Combined with manganese-enhancement, T1 mapping should enable the detection of earlier alternations in myocardial calcium handling as a marker of cellular dysfunction and provide more specific tissue characterisation than the more generalised extracellular and intravascular assessment provided by late-gadolinium enhancement. This study could be used as a stepping stone in cardiovascular research to further the use of MEMRI in different cardiac conditions.

-Improved knowledge base within general research community: Manganese has shown promise in various applications not only using MR technology. The major limitation in the past has been related to its toxicity. Previous studies using manganese have demonstrated its safety in humans. Our study will be exploring the use of manganese further, in different patient cohorts to solidify its use as a contrast agent. This will promote research in different medical specialties such as endocrinology, ophthalmology and neurology where animal studies showed significant promise.

-Policy making: Changes in clinical practice are often evidence driven. We hope to gain better understanding about the mechanisms involved in different cardiomyopathies in the acute phase, but also after recovery. This has the potential to, not only guide complex percutaneous intervention (PCI) in ischemic heart disease but also optimise heart failure treatment in different cardiomyopathies. National and international (NHS,NICE,ESC) policymakers will be provided with clear evidence of impact of MEMRI in ischaemic and takotsubo cardiomyopathy. This will enable them to make informed decisions about guidelines with potential changes in heart failure management and the introduction of manganese enhance MR imaging.

-Improved quality of life (QOL): Heart failure is a global pandemic affecting at least 26 million people worldwide. Despite the significant advances in therapies and prevention, mortality and morbidity are still high, and QOL poor. New knowledge that we gain from better understanding of underlying mechanisms involved in the pathophysiology of different cardiomyopathies may lead to changes in patient care and improvement in QOL.

-Public Education: We hope to better understand reversible cardiomyopathies through this study. This can be used to educate patients and the public about conditions such as Takotsubo cardiomyopathy that we do not understand.

-Health burden: Heart failure imposes both direct costs to healthcare systems and indirect costs to society through morbidity, unpaid care costs, premature mortality and lost productivity. As well as improving QOL, better understanding of pathophysiological mechanisms and being able to identify left ventricular dysfunction accurately may lead to early detection and treatment of those with heart failure thus reducing its economic burden.