Cardiopedia-Ligand: a Ligand Stimulation Atlas for Cardiac Function and Transcriptional Response

Large-scale perturbation atlases have transformed systems biology, yet no equivalent resource exists for the human heart, where contractile function and transcriptomic state must be measured together. Here, we establish Cardiopedia-Ligand, a comprehensive perturbation–function–transcriptome atlas generated by stimulating human cardiac organoids (hCOs) with 87 ligands targeting 98 cell-membrane receptors expressed in the human heart. We developed an automated high-throughput pipeline enabling individualized contractility measurements and single-organoid mRNA-sequencing. We use this pipeline to define both recognized and previously unrecognized functional and transcriptional clusters, including inotropes, endothelin peptides, extracellular matrix regulators, and multiple inflammatory clusters. Clustering analysis, machine learning, and ‘fingerprinting’ of human heart failure biopsies revealed previously underappreciated similarities between ligands and an interferon-γ signaling signature driving heart failure with preserved ejection fraction (HFpEF). Together this comprehensive Cardiopedia-Ligand dataset provides a valuable and accessible resource to interrogate cardiac biology and human disease.