GC and heart failure: The cyclic GMP (cGMP) intracellular signaling pathway attenuates pathologic cardiac hypertrophy and remodeling in experimental models of heart failure and is upregulated by a number of established and investigational treatments of heart failure.1–14 However, the molecules that mediate the cGMP antiremodeling effect remain unknown.15 In the heart, cGMP is synthesized by guanylate cyclase (GC), which can be activated at the cell membrane by natriuretic peptides or in the cytosol by nitric oxide (NO) (reviewed in 16).