Although the heart is usually considered to be a homogeneous organ, it is composed of different cell types that closely interact to maintain homoeostasis. Clearly, the largest volume is occupied by cardiomyocytes but, when it comes to numbers, the other cell types take the upper hand. This drives to a delicate and intricate network of interactions that usually support the action of cardiomyocytes and help to maintain organ function. However, who is a friend in healthy conditions, might turn out to be a foe in other situations. In multiple cardiac pathologies, heterotypic intercellular interactions significantly contribute to the evolution of the disease with multiple and often highly sophisticated actions. Knowledge about the details of such dialogue between the contractile machinery and endothelial cells, leucocytes, fibroblasts, adipocytes, or neurons is only now starting to emerge in its full complexity. Given the crucial role of these interactions in the maintenance of tissue integrity and in the response to noxious conditions, this knowledge is of critical translational importance. The large number of the extracellular signals and the intracellular pathways evoked represent potential drug targets. Therefore, the definition of the network of heterotypic cellular interactions in heart diseases is currently an advanced frontier of drug discovery.

The current Spotlight issue provides a state-of-the-art description of the cell types involved, the signals produced, and the cellular responses elicited and expands on different concepts, models, and disease conditions, with particular focus on ischaemic heart disease and myocardial infarction, remodelling, and heart failure. The different contributions illustrate the complexity of the system as well as how this intricate network can be tackled. Figure 1 gives an overview of the different crosstalk pathways that are discussed.