Metformin inhibits proliferation of residing fibroadipogenic progenitor cells from failing human hearts
Abstract
Introduction: 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.
Methods: 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.
Results: 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…
How strong is the evidence?
Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design.
Read the paper
Related studies
- Metformin as an adjuvant in breast cancer treatment
- Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?
- Aberrant HSF1 signaling activation underlies metformin amelioration of myocardial infarction in mice
- Metformin induces ZFP36 by mTORC1 inhibition in cervical cancer-derived cell lines
- Protein Interaction Network for Identifying Vascular Response of Metformin (Oral Antidiabetic)
- Preventing Long COVID With Metformin
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.