Ion Channels in Cardiac Non-Excitable Cells: From Single-Cell Atlases to Disease.

Cardiovascular disease is shaped not only by cardiomyocyte excitability but also by electrophysiological and membrane-signaling programs in cardiac fibroblasts, endothelial cells, mural cells, immune cells, and adipocytes. Recent single-cell RNA sequencing, spatial transcriptomic, and disease-atlas studies have revealed broad expression of ion-channel transcripts across these non-excitable cardiac cell populations. However, transcript detection alone does not establish functional channel activity, cell-state specificity, or therapeutic relevance. This narrative Review therefore focuses on mechanistically supported channel-cell-disease axes rather than providing an exhaustive catalogue of ion channels detected in cardiac non-myocytes. We synthesize evidence for mechanosensitive channels, transient receptor potential channels, calcium-entry pathways, acid-sensing channels, and potassium, sodium, and chloride channels, as well as connexin hemichannels and pannexin channels. We emphasize studies in which omics-based channel nomination is supported by functional validation through electrophysiology, Ca2+ imaging, mechanostimulation, pharmacological intervention, or cell-selective genetic perturbation. Particular attention is given to mechanisms linking mechanical stress, Ca2+ entry, membrane potential, cell-volume regulation, ATP release, immune activation, vascular tone, fibrosis, and metabolic dysfunction. We also identify key evidence gaps where expression-based observations require direct functional testing in human tissues and disease-relevant cardiac models. By distinguishing atlas-level association from causal channel function, this Review provides a framework for prioritizing non-myocyte ion-channel mechanisms as therapeutic targets in cardiovascular diseases.