Pokreisz et al. recently published an interesting article in which they show increased cardiac left ventricular phosphodiesterase-5A (PDE5A) expression in patients with heart failure. They also generated a PDE5A transgenic mouse in which overexpression of this cGMP-selective phosphodiesterase worsened ventricular remodeling and function after myocardial infarction. Therefore, the obvious conclusion seems to be that inhibition of PDE5A might protect against postmyocardial infarction remodeling. Although the authors show cGMP to be related to these cardiac architectural changes, they raise new questions about the possible cGMP downstream signaling mechanisms involved.