Heart failure (HF) is an important global health problem with great socioeconomic burden. Outcomes remain sub-optimal. Endothelium-cardiomyocyte interactions play essential roles in cardiovascular homeostasis, and deranged endothelium-related signalling pathways have been implicated in the pathophysiology of HF. In particular, disturbances in nitric oxide (NO)-mediated pathway and neuregulin-mediated pathway have been shown to contribute to the development of HF. These signalling pathways hold the potential as pathophysiological targets for new HF therapies, and may aid in patient selection for future HF trials.