Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiac hypertrophy and heart failure

In this Review, Fischmeister and colleagues describe cAMP and cGMP signalling in cardiomyocytes and summarize the various phosphodiesterase (PDE) families expressed in the heart and how they are modified in heart failure. They also assess the potential use of inhibitors or activators of specific PDEs to treat heart failure. Cyclic nucleotide phosphodiesterases (PDEs) modulate the neurohormonal regulation of cardiac function by degrading cAMP and cGMP. In cardiomyocytes, multiple PDE isozymes with different enzymatic properties and subcellular localization regulate local pools of cyclic nucleotides and specific functions. This organization is heavily perturbed during cardiac hypertrophy and heart failure (HF), which can contribute to disease progression. Clinically, PDE inhibition has been considered a promising approach to compensate for the catecholamine desensitization that accompanies HF. Although PDE3 inhibitors, such as milrinone or enoximone, have been used clinically to improve systolic function and alleviate the symptoms of acute HF, their chronic use has proved to be detrimental. Other PDEs, such as PDE1, PDE2, PDE4, PDE5, PDE9 and PDE10, have emerged as new potential targets to treat HF, each having a unique role in local cyclic nucleotide signalling pathways. In this Review, we describe cAMP and cGMP signalling in cardiomyocytes and present the various PDE families expressed in the heart as well as their modifications in pathological cardiac hypertrophy and HF. We also appraise the evidence from preclinical models as well as clinical data pointing to the use of inhibitors or activators of specific PDEs that could have therapeutic potential in HF.

Automated summary

This review discusses the roles of cAMP and cGMP signaling in cardiomyocytes and the various PDE families expressed in the heart, as well as their modifications in pathological cardiac hypertrophy and heart failure. The potential use of specific PDE inhibitors or activators as therapeutic targets in heart failure is also evaluated.