Single-Cell Reconstruction of Progression Trajectory Reveals Intervention Principles in Pathological Cardiac Hypertrophy

BACKGROUND: Pressure overload-induced pathological cardiac hypertrophy is a common predecessor of heart failure, the latter of which remains a major cardiovascular disease with increasing incidence and mortality worldwide. Current therapeutics typically involve partially relieving the heart's workload after the onset of heart failure. Thus, more pathogenesis-, stage-, and cell type-specific treatment strategies require refined dissection of the entire progression at the cellular and molecular levels. METHODS: By analyzing the transcriptomes of 11,492 single cells and identifying major cell types, including both cardiomyocytes and noncardiomyocytes, on the basis of their molecular signatures, at different stages during the progression of pressure overload-induced cardiac hypertrophy in a mouse model, we characterized the spatiotemporal interplay among cell types, and tested potential pharmacological treatment strategies to retard its progression in vivo. RESULTS: We illustrated the dynamics of all major cardiac cell types, including cardiomyocytes, endothelial cells, fibroblasts, and macrophages, as well as those of their respective subtypes, during the progression of disease. Cellular crosstalk analysis revealed stagewise utilization of specific noncardiomyocytes during the deterioration of heart function. Specifically, macrophage activation and subtype switching, a key event at middle-stage of cardiac hypertrophy, was successfully targeted by Dapagliflozin, a sodium glucose cotransporter 2 inhibitor, in clinical trials for patients with heart failure, as well as TD139 and Arglabin, two anti-inflammatory agents new to cardiac diseases, to preserve cardiac function and attenuate fibrosis. Similar molecular patterns of hypertrophy were also observed in human patient samples of hypertrophic cardiomyopathy and heart failure. CONCLUSIONS: Together, our study not only illustrated dynamically changing cell type crosstalk during pathological cardiac hypertrophy but also shed light on strategies for cell type- and stage-specific intervention in cardiac diseases.