Cyclic nucleotide phosphodiesterases (PDEs) modulate the neuro-hormonal 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 was once considered a promising approach to compensate for the catecholamine desensitization that accompanies HF. Although PDE3