Store-Operated Cyclic AMP Signalling (SOcAMPS) represents a novel signalling mechanism in which depletion of Ca²⁺ in the endoplasmic reticulum (ER) leads to a STIM1 (Stromal Interaction Molecule 1)-dependent increase in cAMP levels, independently of cytosolic Ca²⁺. Here we evaluated whether SOcAMPS was manifest in neonatal rat ventricular myocytes (NRVM) and human "iCardiomyocytes" and its potential role in cardiac cell hypertrophy. cAMP and ER [Ca²⁺] were monitored by live cell fluorescence imaging after transfection with the FRET-based probes, EPACH30 and D1ER cameleon, respectively. The low affinity Ca²⁺ chelator, TPEN (1mM), able to induce a reduction of SR Ca²⁺ levels without affecting cytosolic [Ca²⁺], elicited a significant cAMP increase in the absence and presence of 5 mM forskolin (FRSK) in both NRVM and human iCardiomyocytes. SR depletion by ionomycin (10 mM) was found to exert similar effects, independently of cytosolic Ca²⁺. The participation of STIM1 in the observed phenomenon was established in NRVMs by the 47% reduction of the [cAMP] response obtained after shRNA-mediated knockdown of STIM1. Interestingly, a significant increase of the TPEN+FRSK-stimulated response was found following "in vitro" induction of cell hypertrophy. These data establish, for the first time, the existence of SOcAMPS in these two cardiac cell models, and suggest a potential role for this new signalling mechanism in cardiac cell hypertrophy.