Mineralocorticoid receptor antagonists (MRAs) reduce morbidity and mortality in 
chronic heart failure. Novel nonsteroidal MRAs are currently developed and need 
to be pharmacologically characterized in comparison to classical steroidal MRAs. 
A mouse model of cardiac fibrosis induced by short-term isoproterenol injection 
was used to compare the nonsteroidal MRA finerenone and the steroidal MRA 
eplerenone in equi-efficient systemic MR blocking dosages. Molecular mechanisms 
were studied in MR-expressing H9C2/MR+ cardiomyocytes and in MR transcriptional 
cofactor binding assays. Both MRAs significantly inhibited an 
isoproterenol-mediated increase of left ventricular mass. Isoproterenol-induced 
cardiac fibrosis and macrophage invasion were potently blocked by finerenone, 
whereas eplerenone had no significant effect. Speckle tracking echocardiography 
revealed a significant improvement of global longitudinal peak strain by 
finerenone, an effect less prominent with eplerenone. Antifibrotic actions of 
finerenone were accompanied by a significant inhibition of profibrotic cardiac 
TNX (tenascin-X) expression, a regulation absent with eplerenone. Finally, we 
show a higher potency/efficacy and inverse agonism of finerenone versus 
eplerenone in MR transcriptional cofactor binding assays indicating differential 
MR cofactor modulation by steroidal and nonsteroidal MRAs. This study 
demonstrates that the nonsteroidal MRA finerenone potently prevents cardiac 
fibrosis and improves strain parameters in mice. Cardiac antifibrotic actions of 
finerenone may result from the inhibition of profibrotic TNX gene expression 
mediated by differential MR cofactor binding. Selective MR cofactor modulation 
provides a molecular basis for distinct (pre)-clinical actions of nonsteroidal 
and steroidal MRAs.