Metformin inhibits proliferation of residing fibroadipogenic progenitor cells from failing human hearts.

Evidence from randomized trials indicates beneficial effects of metformin treatment in heart failure with reduced ejection fraction (HFrEF), but mechanisms of action remain elusive. We investigated myocardial metformin distribution in vivo in HFrEF patients and explored its effects on cardiac fibrogenic progenitor cells from human HFrEF hearts in vitro. We assessed myocardial metformin distribution and its dependency on myocardial viability in seven HFrEF patients (ejection fraction: 36 ± 8%; median age: 67 years) using 11C-metformin positron emission tomography (PET), 15O-H2O-PET, and exercise stress echocardiography. We characterized myocardial cellular composition by fluorescence-activated cell sorting and single-cell RNA sequencing (scRNA-seq) on mononuclear cells isolated from explanted left ventricles from four HFrEF patients and four control human hearts. A population of fibroadipogenic progenitor cells (FAPs) was identified and incubated after differentiation with metformin to test the effects on proliferation. Myocardial 11C-metformin kinetics were best described by reversible two-tissue-compartment kinetics. Global myocardial metformin net influx rate was 0.012 ± 0.007 ml ml-1 min-2, and the myocardium-to-blood ratio was 1.24 (95% confidence intervals: 1.03-1.44; P < .001) after 90 min. Regional myocardial metformin net influx correlated inversely with myocardial viability (r = -0.65, P = .04). By scRNA-seq, we identified cardiac FAPs expressing CD34 and PDGFRA, which transformed into extracellular matrix-forming myogenic cells upon activation. Incubation with metformin in clinically relevant doses (0.1 mM) inhibited FAP proliferation by 25%. Myocardial metformin uptake in HFrEF is marginal and confined to less viable and fibrotic regions. Cardiac FAPs are resident in human HFrEF myocardium and exhibit fibrogenic potential. Metformin inhibits FAP activation and proliferation at clinically relevant concentrations. These findings suggest that metformin may attenuate adverse left ventricular remodelling by targeting cardiac FAPs. https://clinicaltrials.gov. Unique identifier: NCT03122769.