Herein, we employed in vitro and in vivo models and unique transgenic strains with cardiomyocyte (cmCNP−/−), endothelial (ecCNP−/−), and fibroblast (fbCNP−/−)—specific CNP deletion, to define the peptide as a critical player in cardiac structure, ventricular contractility, and coronary reactivity; additionally, proof-of-concept is demonstrated for pharmacological targeting of this novel pathway in HF and ischaemia cardiovascular disorders. Here, CNP is linked to hydrops fetalis.