Turning on cGMP-dependent pathways to treat cardiac dysfunctions: boom, bust, and beyond.

•The presence of PDE5 in murine CMs has been questioned by recent studies.•Clinical trials testing PDE5 inhibition for different cardiac disease settings has failed.•Effects of the PDE5 inhibitor sildenafil on non-myocyte cardiac cells need to be better evaluated.•Favorable effects of cGMP/cGKI in the heart are under the control of a large set of PDEs.•Antifibrotic effects of PDE5 inhibition and elevated cGMP likely stem from myofibroblasts/fibroblasts and require cGKI.