Heart Failure (HF) remains a leading cause of hospitalizations and mortality. Treatment is symptomatic and unsatisfactory for some patients (notably patients suffering from HF with preserved ejection fraction), thus urging for innovative approaches to reverse the course of ventricular dysfunction. cAMP and its effector PKA are key regulators of cardiac function and inappropriate activation of this pathway is a hallmark of HF. Current treatment targeting cAMP/PKA signalling presents with limitations: β-blockers are not effective in some patients and cAMP raising agents to treat acute HF are associated with arrhythmias and increased mortality. The reasons for the disappointing performance of these drugs are unclear, revealing our limited understanding of the role of this pathway in the pathophysiology of the heart. In addition to its role as regulator of the chronotropic, inotropic and lusitropic response to catecholamines, cAMP affects multiple other functions including, among others, cell growth, metabolism and death. This complex functional role is achieved via modulation of ion fluxes at membranes and of myofilament sensitivity to Ca2+ as well as via regulation of transcription factors and a variety of enzymes and other targets. A key question remains how coordination is achieved among the complex cAMP signalling networks. In recent years we1-2 and others3-4 have demonstrated that cAMP signalling is compartmentalised. Compartmentalised signalling allows individual GPCRs to generate distinct cAMP pools that, in turn, activate defined subsets of localized PKA that are tethered in proximity to specific targets via binding to A kinase anchoring proteins (AKAPs). Posphodiesterases (PDEs), a superfamily of enzymes that degrade cAMP and that includes more than 50 isoforms presenting unique regulation and subcellular localisation features, play a key role in the spatial regulation of cAMP propagation, and regulate cAMP levels within individual compartments. Thus, displacement of individual PDE isoforms from their subcellular anchor site results in local elevation of cAMP5. Compartmentalisation of cAMP signalling has important implications for cardiac physiology and pathophysiology6. Yet, the size and location of distinct cAMP domains, the amplitude and kinetics of the cAMP signal within each domain, their functional role and the coordination of signalling between different domains, remain largely to be defined. Understanding the details of such organisation is the current challenge in the field. Compartmentalisation of cAMP prompts the idea that with a detailed understanding of the organization, regulation and function of individual cAMP compartments it may be possible to target individual cAMP pools, rather than global intracellular cAMP levels, in order to achieve greater therapeutic efficacy and specificity7. Real-time imaging of cAMP using fluorescence resonance energy transfer (FRET)-based reporters has enhanced our understanding of compartmentalised cAMP signalling1,2,4. However, major drawbacks have been the limited resolution of the FRET probes and the difficulty to directly compare cAMP signals generated at different intracellular sites. We have recently generated a novel FRET-based sensor (named CUTie, for cAMP Universal Tag for imaging experiments) that detects compartmentalised cAMP with unprecedented spatial resolution. Using CUTie, we have quantitatively measured cAMP in situ in the immediate vicinity of specific multiprotein complexes involved in excitation-contraction coupling (EEC). We demonstrated that the cardiac response to b-AR stimulation generates cAMP signals with distinct local amplitude and kinetics and that the size of such domains is in the nanometre range, at least one order of magnitude smaller than previously thought. We demonstrated that such nano-heterogeneity of the cAMP signal depends on differential local activity of PDEs. Importantly, we found that the local coordination of cAMP signals is necessary to maximize the adrenergic effect on contractility but, at the same time, it results in vulnerability of the myofilaments to Ca2+ sensitization. In conditions of low adrenergic input, as found in HF, the difference in the cAMP response at different sites becomes more extreme with no effective signal being generated at specific sites, which may underpin the diastolic dysfunction associated with HF. The nanoscopic dimension of cAMP signalling revealed by our recent work provides a new framework for understanding cardiac adrenergic signalling and for the development of novel approaches to therapeutic intervention.