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 etiology-, stage-, and cell type-specific treatment strategies require refined dissection of the entire progression at the cellular and molecular level.

Methods

By analyzing the transcriptomes of 11,492 single cells and identifying major cell types, including both cardiomyocytes and non-cardiomyocytes, based on their molecular signatures, at different stages during the progression of pressure overload-induced cardiac hypertrophy in a mouse model, we characterized the spatiotemporal interplay amongst cell types, and tested potential pharmacologic 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 non-cardiomyocytes 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 co-transporter 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. Importantly, 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