Abstract Background Delayed-enhancement magnetic resonance imaging (DEMRI) with gadolinium detects macroscopic myocardial fibrosis, but does not directly assess myocardial function. Manganese, a paramagnetic calcium-analogue, enables direct dynamic assessment myocyte calcium handling and is a potential early marker of myocardial dysfunction. We have previously demonstrated manganese-enhanced MRI (MEMRI) can detect altered calcium-handling in remote remodelling myocardium in a rodent infarct model. Purpose To evaluate MEMRI as a marker of altered myocardial calcium handling in patients with non-ischaemic cardiomyopathy (NCT03607669). Methods Healthy volunteers (HV, n=20, 13 male, 42±11 years) and patients with hypertrophic (HCM, n=11, 5 male, 57±15 years) or dilated (DCM, n=5, 3 male, 56±14 years) cardiomyopathies underwent both DEMRI and MEMRI. Myocardial T1 was measured for 40 min after intravenous manganese dipyridoxyl diphosphate (Mn-DPDP, 5 μmol/kg) administration. Images were acquired at 3T with T1 imaging performed using Shortened Modified Look-Locker Inversion recovery [Figure A] (WIP #1048 Siemens Healthcare Ltd). Results No adverse effects were observed. In HV, the myocardialT1 profile following Mn-DPDP administration demonstrated a rapid initial descent (perfusion phase) followed by a slower, more gradual decrease which continued throughout the 40 min imaging period (mean reduction 25.2%, 283±9ms). In patients with HCM, T1 values followed a different pattern following Mn-DPDP administration. In areas of focal myocardial fibrosis (defined by DEMRI) there was again a sharp initial shortening of T1 but this was followed by a steady increase towards baseline, which eventually recovered to >40% of its initial value at 40 minutes. In areas of diffuse myocardial fibrosis, the initial shortening in the perfusion phase was followed by a more gradual recovery which then plateaued, remaining stable at 21% of native T1 by 40 min [Figure B]. Hypertrophied non-fibrosed myocardium had higher native T1 than HV (1178±45 vs 1133±36 ms P=0.005) and the rate of T1 reduction following the perfusion phase was slower (P=0.0005), leading to less overall T1 shortening at 40 min (880±40 vs 841±28 ms, P=0.004, [Figure C]). No patient with DCM had fibrosis by DEMRI. Native T1 was higher than HV (1234±26 vs 1133±36 ms, P<0.0001) and the rate of T1 reduction following the perfusion phase was lower in DCM myocardium (P<0.0001) resulting in less overall T1 shortening at 40 min (914±60 vs 841±28 ms, P=0.0006, [Figure D]). MEMRI in non-ischaemic cardiomyopathy Conclusion MEMRI identifies altered calcium-handling in pathological myocardium of non-ischaemic cardiomyopathy, irrespective of fibrosis by DEMRI. This feasible, safe and novel method of functional myocardial tissue characterisation has exciting potential for future diagnostic, functional and clinical applications. Acknowledgement/Funding British Heart Foundation