Preclinical models indicate that PDE5 is more involved in regulating GC-1/2 signalling (e.g. in erectile dysfunction), whereas PDE9 and PDE2 are biased towards NP signalling (e.g. in heart failure).29,140 It remains to be seen whether some of the negative clinical studies (e.g. cinaciguat and sildenafil in heart failure) can be explained by the use of a suboptimal cGMP-modulating therapy.77,121 However, such combinations may also be contraindicated in one setting and indicated in another. Here, PDE5A is linked to heart failure.